Blas Frangione, Ph.D., M.D.

Greater risk of Alzheimer's disease in older adults with insomnia
Osorio, Ricardo S; Pirraglia, Elizabeth; Aguera-Ortiz, Luis F; During, Emmanuel H; Sacks, Hayley; Ayappa, Indu; Walsleben, Joyce; Mooney, Anne; Hussain, Asad; Glodzik, Lidia; Frangione, Blas; Martinez-Martin, Pablo; de Leon, Mony J
2011 Mar;59(3):559-562, Journal of the American Geriatrics Society
— id: 134223, year: 2011, vol: 59, page: 559, stat: Journal Article,

CEREBRAL AMYLOID ANGIOPATHY AND ALZHEIMER'S DISEASE
Ghiso J; Tomidokoro Y; Revesz T; Frangione B; Rostagno A
2010 Jul 8;61(Suppl):S111-S124, Hirosaki igaku = Hirosaki medical journal
Cerebral amyloid angiopathy (CAA) is increasingly recognized as a major contributor of Alzheimer's disease (AD) pathogenesis. To date, vascular deposits and not parenchymal plaques appear more sensitive predictors of dementia. Amyloid deposition in and around cerebral blood vessels plays a central role in a series of response mechanisms that lead to changes in the integrity of the blood-brain barrier, extravasations of plasma proteins, edema formation, release of inflammatory mediators and matrix metalloproteases which, in turn, produce partial degradation of the basal lamina with the potential to develop hemorrhagic complications. The progressive buildup of amyloid deposits in and around blood vessels chronically limits blood supply and causes focal deprivation of oxygen, triggering a secondary cascade of metabolic events several of which involve the generation of nitrogen and oxygen free radicals with consequent oxidative stress and cell toxicity. Many aspects of CAA in early- and late-onset AD -the special preference of Abeta40 to deposit in the vessel walls, the favored vascular compromise associated with many Abeta genetic variants, the puzzling observation that some of these vasculotropic variants solely manifest with recurrent hemorrhagic episodes while others are mainly associated with dementia- await clarification. Non-Abeta cerebral amyloidoses reinforce the viewpoint that plaque burden is not indicative of dementia while highlighting the relevance of nonfibrillar lesions and vascular involvement in the disease pathogenesis. The lessons learned from the comparative study of Abeta and non-Abeta cerebral amyloidosis provide new avenues and alternative models to study the role of amyloid in the molecular basis of neurodegeneration
— id: 138253, year: 2010, vol: 61, page: S111, stat: Journal Article,

PYROGLUTAMATE FORMATION AT THE N-TERMINI OF ABRI MOLECULES IN FAMILIAL BRITISH DEMENTIA IS NOT RESTRICTED TO THE CENTRAL NERVOUS SYSTEM
Tomidokoro Y; Tamaoka A; Holton JL; Lashley T; Frangione B; Revesz T; Rostagno A; Ghiso J
2010 Jul 8;61(Suppl):S262-S269, Hirosaki igaku = Hirosaki medical journal
Amyloid molecules harboring pyroglutamate (pGlu) residue at the N-termini are considered to be important for the development of cerebral amyloidosis such as Alzheimer's disease and thought to be either spontaneously generated or being catalyzed by glutaminyl cyclase. Familial British dementia (FBD) is an autosomal dominant form of dementia neuropathologically characterized by parenchymal amyloid and preamyloid deposits, extensive cerebral amyloid angiopathy, and neurofibrillary tangles. FBD is caused by a stop to Arg mutation in the BRI2 gene, generating de novo created amyloid molecule ABri which accumulates in FBD brains but is not present in the normal population. Soluble ABri molecules present in the circulation of carriers of the BRI2 mutation are 34 amino acids long exclusively harboring Glu residue at the N-termini (ABri1-34E), whereas water- and formic acid-soluble ABri molecules extracted from FBD brains have abundant ABri species bearing pGlu residue (ABri1-34pE), suggesting that pyroglutamate formation occurs at the site of deposition. In order to further clarify the mechanism (s) of ABri deposition, we studied whether pyroglutamate formation indeed occurs outside the central nervous system taking advantage that FBD is also a systemic amyloidosis. Soluble and fibrillar ABri molecules extracted from systemic organs and analyzed biochemically using a combination of immunoprecipitation, mass spectrometry, and western blot analysis were oligomeric in size and contained a large proportion of ABri1-34pE. The data indicate that pyroglutamate formation at the N-termini of ABri molecules is an early step in the process of FBD amyloid deposition, and its formation is not restricted to the central nervous system
— id: 138254, year: 2010, vol: 61, page: S262, stat: Journal Article,

Iowa variant of familial Alzheimer's disease: accumulation of posttranslationally modified AbetaD23N in parenchymal and cerebrovascular amyloid deposits
Tomidokoro, Yasushi; Rostagno, Agueda; Neubert, Thomas A; Lu, Yun; Rebeck, G William; Frangione, Blas; Greenberg, Steven M; Ghiso, Jorge
2010 Apr;176(4):1841-1854, American journal of pathology
Mutations within the amyloid-beta (Abeta) sequence, especially those clustered at residues 21-23, which are linked to early onset familial Alzheimer's disease (AD), are primarily associated with cerebral amyloid angiopathy (CAA). The basis for this predominant vascular amyloid burden and the differential clinical phenotypes of cerebral hemorrhage/stroke in some patients and dementia in others remain unknown. The AbetaD23N Iowa mutation is associated with progressive AD-like dementia, often without clinically manifested intracerebral hemorrhage. Neuropathologically, the disease is characterized by predominant preamyloid deposits, severe CAA, and abundant neurofibrillary tangles in the presence of remarkably few mature plaques. Biochemical analyses using a combination of immunoprecipitation, mass spectrometry, amino acid sequence, and Western blot analysis performed after sequential tissue extractions to separately isolate soluble components, preamyloid, and fibrillar amyloid species indicated that the Iowa deposits are complex mixtures of mutated and nonmutated Abeta molecules. These molecules exhibited various degrees of solubility, were highly heterogeneous at both the N- and C-termini, and showed partial aspartate isomerization at positions 1, 7, and 23. This collection of Abeta species-the Iowa brain Abeta peptidome-contained clear imprints of amyloid clearance mechanisms yet highlighted the unique neuropathological features shared by a non-Abeta cerebral amyloidosis, familial Danish dementia, in which neurofibrillary tangles coexist with extensive pre-amyloid deposition in the virtual absence of fibrillar lesions. These data therefore challenge the importance of neuritic plaques as the sole contributors for the development of dementia
— id: 108922, year: 2010, vol: 176, page: 1841, stat: Journal Article,

Diminished Amyloid-beta Burden in Tg2576 Mice Following a Prophylactic Oral Immunization with a Salmonella-Based Amyloid-beta Derivative Vaccine
Boutajangout, Allal; Goni, Fernando; Knudsen, Elin; Schreiber, Fernanda; Asuni, Ayodeji; Quartermain, David; Frangione, Blas; Chabalgoity, Alejandro; Wisniewski, Thomas; Sigurdsson, Einar M
2009 Jan 1;18(4):961-972, Journal of Alzheimer's Disease
Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. Prior to the side effects in the first Elan/Wyeth AD vaccine trial, we proposed using amyloid-beta (Abeta) derivatives as a safer approach. The route of administration may also affect vaccine safety. To assess the feasibility of oral immunization that promotes mucosal immunity, Tg2576 AD model mice were treated prophylactically three times over 6 weeks starting at 3-5 months of age with a Salmonella vaccine expressing K6Abeta<formula> _{1-30}</formula>. At 22-24 months of age, cortical Abeta plaque burden and total Abeta<formula>_{40}</formula>/<formula>_{42}</formula> levels were reduced by 48-75% in the immunized mice compared to controls, which received unmodified Salmonella. Plaque clearance was not associated with increased microglial activation which may be explained by the long treatment period. Furthermore, cerebral microhemorrhages were not increased in the treated mice in contrast to several passive Abeta antibody studies. These results further support our findings with this immunogen delivered subcutaneously and demonstrate its efficacy when given orally which may provide added benefits for human use
— id: 107413, year: 2009, vol: 18, page: 961, stat: Journal Article,

Synthetic immunogenic but non-deposit-forming polypeptides and peptides homologous to amyloid beta, prion protein, amylin, alpha-synuclein, or polyglutamine repeats for induction of an immune response thereto
Frangione, Blas; Wisniewski, Thomas; Sigurdsson, Einar M
2009 ;27(7):957-964, Official gazette of the United States Patent & Trademark Office. Patents
The present invention relates to immunogenic but non-depositing-forming polypeptides or peptides homologous to amyloid beta, prion, amylin or alpha-synuclein which can be used alone or conjugated to an immunostimulatory molecule in an immunizing composition for inducing an immune response to amyloid beta peptides and amyloid deposits, to prion protein and prion deposits, to amylin and amylin deposits, to alpha-synuclein and deposits containing alpha-synuclein, or to polyglutamine repeats and deposits of proteins containing polyglutamine repeats. Described are also antibodies directed against such peptides, their generation, and their use in methods of passive immunization to such peptides and deposits
— id: 97983, year: 2009, vol: 27, page: 957, stat: Journal Article,

Erratum: Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies (Acta Neuropathologica (2009) vol. 118 (115-130) 10.1007/s00401-009-0501-8)
Revesz T.; Holton J.L.; Lashley T.; Plant G.; Frangione B.; Rostagno A.; Ghiso J.
2009 ;118(2):321-, Acta neuropathologica
— id: 101651, year: 2009, vol: 118, page: 321, stat: Journal Article,

Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies
Revesz, Tamas; Holton, Janice L; Lashley, Tammaryn; Plant, Gordon; Frangione, Blas; Rostagno, Agueda; Ghiso, Jorge
2009 Jul;118(1):115-130, Acta neuropathologica
In cerebral amyloid angiopathy (CAA), amyloid fibrils deposit in walls of arteries, arterioles and less frequently in veins and capillaries of the central nervous system, often resulting in secondary degenerative vascular changes. Although the amyloid-beta peptide is by far the commonest amyloid subunit implicated in sporadic and rarely in hereditary forms of CAA, a number of other proteins may also be involved in rare familial diseases in which CAA is also a characteristic morphological feature. These latter proteins include the ABri and ADan subunits in familial British dementia and familial Danish dementia, respectively, which are also known under the umbrella term BRI2 gene-related dementias, variant cystatin C in hereditary cerebral haemorrhage with amyloidosis of Icelandic-type, variant transthyretins in meningo-vascular amyloidosis, disease-associated prion protein (PrP(Sc)) in hereditary prion disease with premature stop codon mutations and mutated gelsolin (AGel) in familial amyloidosis of Finnish type. In this review, the characteristic morphological features of the different CAAs is described and the implication of the biochemical, genetic and transgenic animal data for the pathogenesis of CAA is discussed
— id: 92856, year: 2009, vol: 118, page: 115, stat: Journal Article,

Antibody response and plasma Abeta1-40 levels in young Microcebus murinus primates immunized with Abeta1-42 and its derivatives
Trouche, Stephanie G; Asuni, Ayodeji; Rouland, Sylvie; Wisniewski, Thomas; Frangione, Blas; Verdier, Jean-Michel; Sigurdsson, Einar M; Mestre-Frances, Nadine
2009 Feb 11;27(7):957-964, Vaccine
We have been developing Abeta derivative vaccines with the objective to improve the safety of Abeta targeting immunotherapy. Our Abeta homologs are designed to have less direct toxicity and to produce a modified immune response compared to Abeta. In extensive mouse studies, all our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for studies in old primates and for human trials we assessed their effect in young lemur primates (n=25) that with age develop Abeta plaques and tau aggregates as seen in Alzheimer's disease. In the primates, all the peptides administered with alum adjuvant elicited a moderate to robust anti-Abeta IgM response. Abeta1-42, K6Abeta1-30 and K6Abeta1-30[E(18)E(19)] resulted in a high anti-Abeta IgG response, whereas Abeta1-30[E(18)E(19)] produced a weaker more variable IgG titer. Notably, 22 weeks after the 3rd immunization, IgM and IgG levels in derivative-vaccinated primates were similar to preimmune values whereas Abeta1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized Abeta1-40 often correlated with increase in Abeta1-40 in plasma, which suggests that the antibodies were binding to Abeta in vivo. Interestingly, significant transient weight gain was observed (K6Abeta1-30-, Abeta1-30[E(18)E(19)]- and Abeta1-42-treated) or a trend in the same direction (K6Abeta1-30[E(18)E(19)]-treated, adjuvant controls) following the injections. Based on these findings, we have chosen K6Abeta1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other Abeta derivatives. Our present findings indicate that most of our Abeta derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach
— id: 91348, year: 2009, vol: 27, page: 957, stat: Journal Article,

Differential apoptotic response of primary human cerebral endothelial cells to oligomeric assemblies of amyloid beta genetic variants
Cam J; Meyerson J; Mezhericher E; Frangione B; Ghiso J; Rostagno A
New trends in Alzheimer and Parkinson related disorders : ADPD 2007 Bologna : Medimond International Proceedings, 2008,
— id: 5118, year: 2008, vol: , page: 141, stat: Chapter,

Synthetic immunogenic but non amyloidogenic peptides homologous to amyloid beta for induction of an immune response to amyloid beta and amyloid deposits
Frangione, Blas; Wisniewski, Thomas; Sigurdsson, Einar M
2008 ;27(7):957-964, Official gazette of the United States Patent & Trademark Office. Patents
The present invention relates to synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid beta which can be used alone or conjugated to an immunostimulatory molecule in an immunizing composition for inducing an immune response to amyloid beta peptides and amyloid deposits
— id: 97982, year: 2008, vol: 27, page: 957, stat: Journal Article,

Expression of BRI2 mRNA and protein in normal human brain and familial British dementia: its relevance to the pathogenesis of disease
Lashley, T; Revesz, T; Plant, G; Bandopadhyay, R; Lees, A J; Frangione, B; Wood, N W; de Silva, R; Ghiso, J; Rostagno, A; Holton, J L
2008 Oct;34(5):492-505, Neuropathology & applied neurobiology
INTRODUCTION: Two different disease-specific mutations in the BRI2 gene, situated on chromosome 13, have been identified as giving rise to familial British dementia (FBD) and familial Danish dementia (FDD). Each mutation results in extension of the open reading frame generating the disease-specific precursor proteins which are cleaved by furin-like proteolysis releasing the amyloidogenic C-terminal peptides ABri and ADan in FBD and FDD, respectively. MATERIAL AND METHODS: To understand the mechanism of the formation of amyloid lesions in FBD, we studied the origin of the precursor proteins and furin in the human brain. We used control brains, cases of sporadic Alzheimer's disease (AD), variant AD with cotton wool plaques and FBD to study BRI2 mRNA expression using in situ hybridization. Furin and BRI2 protein expression was investigated using Western blotting and immunohistochemistry. RESULTS: BRI2 mRNA and BRI2 protein are widely expressed primarily by neurones and glia and are deposited in the amyloid lesions in FBD. They were, however, not expressed by cerebrovascular components. Furin expression showed a similar pattern except that it was also present in cerebrovascular smooth muscle cells. CONCLUSIONS: These findings suggest that neurones and glia and are a major source of BRI2 protein and that in FBD, the mutated precursor protein may undergo furin cleavage within neurones to produce the amyloid peptide ABri. The failure to demonstrate BRI2 in blood vessels under the conditions tested suggests that vascular amyloid peptide production does not contribute significantly to cerebral amyloid angiopathy (CAA) in FBD and FDD, lending indirect support to the drainage hypothesis of CAA
— id: 101670, year: 2008, vol: 34, page: 492, stat: Journal Article,

Differential apoptotic response of primary human cerebral endothelial cells to oligomeric assemblies of amyloid beta genetic variants
Cam J; Meyerson J; Lin H; Frangione B; Ghiso J; Rostagno A
2007 ;4:66-66 #S1, Neuro-degenerative diseases
— id: 73970, year: 2007, vol: 4, page: 66, stat: Journal Article,

Preferential association of serum amyloid P component with fibrillar deposits in familial British and Danish dementias: similarities with Alzheimer's disease
Rostagno, Agueda; Lashley, Tammaryn; Ng, Douglas; Meyerson, Jordana; Braendgaard, Hans; Plant, Gordon; Bojsen-Moller, Marie; Holton, Janice; Frangione, Blas; Revesz, Tamas; Ghiso, Jorge
2007 Jun 15;257(1-2):88-96, Journal of the neurological sciences
Two hereditary forms of cerebrovascular amyloidosis, familial British and Danish dementias (FBD and FDD), share striking similarities with Alzheimer's disease (AD) despite structural differences among their amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD). Neuropathological lesions in these disorders include neurofibrillary tangles, parenchymal amyloid and pre-amyloid deposits and overwhelming cerebral amyloid angiopathy co-localizing with reactive microglia and multiple amyloid associated proteins including activation products of the complement cascade. Immunohistochemical analysis of FBD and FDD brain lesions unveiled the presence of serum amyloid P-component (SAP) primarily associated with thioflavin positive amyloid deposits in spite of the significant pre-amyloid burden existing in both disorders. Using affinity chromatography and ELISA binding assays we demonstrated specific, calcium-dependent, saturable, high affinity binding interactions between SAP and ABri/ADan peptides, with dissociation constant values in the sub-nanomolar range and within the same order of magnitude as those resulting from the interaction of SAP with Alzheimer's Abeta1-40 and Abeta1-42. The preferential association of SAP with fibrillar amyloid lesions and not with non-fibrillar pre-amyloid deposits is puzzling, suggesting that SAP modulates the assembly and stability of the final fibril rather than participating in the early steps of protein misfolding and oligomerization
— id: 73958, year: 2007, vol: 257, page: 88, stat: Journal Article,

A primer of amyloid nomenclature
Westermark, Per; Benson, Merrill D; Buxbaum, Joel N; Cohen, Alan S; Frangione, Blas; Ikeda, Shu-Ichi; Masters, Colin L; Merlini, Giampaolo; Saraiva, Maria J; Sipe, Jean D
2007 Sep;14(3):179-183, Amyloid
The increasing knowledge of the exact biochemical nature of the localized and systemic amyloid disorders has made a logical and easily understood nomenclature absolutely necessary. Such a nomenclature, biochemically based, has been used for several years but the current literature is still mixed up with many clinical and histochemically based designations from the time when amyloid in general was poorly understood. All amyloid types are today preferably named by their major fibril protein. This makes a simple and rational nomenclature for the increasing number of amyloid disorders known in humans and animals
— id: 73908, year: 2007, vol: 14, page: 179, stat: Journal Article,

Novel prion protein conformation and glycotype in Creutzfeldt-Jakob disease
Zanusso, Gianluigi; Polo, Alberto; Farinazzo, Alessia; Nonno, Romolo; Cardone, Franco; Di Bari, Michele; Ferrari, Sergio; Principe, Serena; Gelati, Matteo; Fasoli, Elisa; Fiorini, Michele; Prelli, Frances; Frangione, Blas; Tridente, Giuseppe; Bentivoglio, Marina; Giorgi, Alessandra; Schinina, Maria Eugenia; Maras, Bruno; Agrimi, Umberto; Rizzuto, Nicola; Pocchiari, Maurizio; Monaco, Salvatore
2007 Apr;64(4):595-599, Archives of neurology
OBJECTIVE: To describe a novel molecular and pathological phenotype of Creutzfeldt-Jakob disease. Patient A 69-year-old woman with behavioral and personality changes followed by rapidly evolving dementia. RESULTS: Postmortem examination of the brain showed intracellular prion protein deposition and axonal swellings filled with amyloid fibrils. Biochemical analysis of the pathological prion protein disclosed a previously unrecognized PrP(Sc) tertiary structure lacking diglycosylated species. Genetic analysis revealed a wild-type prion protein gene. The prion agent responsible for this atypical phenotype was successfully passaged to bank voles. CONCLUSION: To our knowledge, our results define a new human prion disorder characterized by intracellular accumulation of a novel type of pathological prion protein
— id: 96089, year: 2007, vol: 64, page: 595, stat: Journal Article,

Vaccination of Alzheimer's model mice with Abeta derivative in alum adjuvant reduces Abeta burden without microhemorrhages
Asuni, Ayodeji A; Boutajangout, Allal; Scholtzova, Henrieta; Knudsen, Elin; Li, Yong Sheng; Quartermain, David; Frangione, Blas; Wisniewski, Thomas; Sigurdsson, Einar M
2006 Nov;24(9):2530-2542, European journal of neuroscience
Abstract Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-beta (Abeta) 1-42, and the adjuvant, QS-21. To avoid this toxicity, we have been using Abeta derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-Abeta burden, Abeta levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Abeta deposit burden by 31% and Abeta levels by 30-37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Abeta burden or improve cognition. Significantly, the immunotherapy in the 11-24 months treatment group, that reduced Abeta burden, did not increase cerebral bleeding or vascular Abeta deposits in contrast to several Abeta antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Abeta burden when used with an adjuvant suitable for humans, without increasing vascular Abeta deposits or microhemorrhages
— id: 69181, year: 2006, vol: 24, page: 2530, stat: Journal Article,

Oligomeric assemblies of the Abeta Dutch mutant induce the formation of nucleosomes in primary cerebral endothelial cells
Cam J; Meyerson JL; Frangione B; Ghiso J; Rostagno A
Alzheimer's disease : new advances Bologna : Medimond International Proceedings, 2006,
— id: 5116, year: 2006, vol: , page: 397, stat: Chapter,

Oligomeric assemblies of the Abeta Dutch mutant induce formation of nucleosomes in primary cerebral endothelial cells
Cam J; Meyerson JL; Ng D; Frangione B; Ghiso J; Rostagno A
2006 ;2:S531-S531, Alzheimer's & Dementia
— id: 101631, year: 2006, vol: 2, page: S531, stat: Journal Article,

Oligomeric assemblies of the A-beta Dutch mutant induces the formation of nucleosomes in primary cerebral endothelial cells
Cam J; Meyerson JL; Ng D; Frangione B; Ghiso J; Rostango A
2006 ;2(3 Suppl 1):S531-S531, Alzheimer's & Dementia
— id: 73968, year: 2006, vol: 2, page: S531, stat: Journal Article,

Post-translational modifications in A-beta and non-A-beta amyloidosis
Ghiso J; Tomidokoro Y; Lashley T; Holton J; Revesz T; Rostagno A; Frangione B
2006 ;2(3 Suppl 1):S479-S479, Alzheimer's & Dementia
— id: 73967, year: 2006, vol: 2, page: S479, stat: Journal Article,

Genetic alterations of the BRI2 gene: familial British and Danish dementias
Ghiso, J; Rostagno, A; Tomidokoro, Y; Lashley, T; Bojsen-Moller, M; Braendgaard, H; Plant, G; Holton, J; Lal, R; Revesz, T; Frangione, B
2006 Jan;16(1):71-79, Brain pathology
Classic arguments sustaining the importance of amyloid in the pathogenesis of dementia are usually centered on amyloid beta (Abeta) and its role in neuronal loss characteristic of Alzheimer disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias, share many aspects of Alzheimer disease, including the presence of neurofibrillary tangles, parenchymal pre-amyloid and amyloid deposits, cerebral amyloid angiopathy, and a widespread inflammatory response. Both early-onset conditions are linked to specific mutations in the BRI2 gene, causing the generation of longer-than-normal protein products and the release of 2 de novo created peptides ABri and ADan, the main components of amyloid fibrils in these inherited dementias. Although the molecular mechanisms and signal transduction pathways elicited by the amyloid deposits and their relation to cognitive impairment remain to be clarified, new evidence indicates that, independent of the differences in their primary structures, Abeta, ABri, and ADan subunits are able to form morphologically compatible ion-channel-like structures and elicit single ion-channel currents in reconstituted lipid membranes. These findings reaffirm the notion that non-Abeta amyloidosis constitute suitable alternative models to study the role of amyloid deposition in the mechanism of neuronal cell death
— id: 64171, year: 2006, vol: 16, page: 71, stat: Journal Article,

Molecular chaperons, amyloid and preamyloid lesions in the BRI2 gene-related dementias: a morphological study
Lashley, T; Holton, J L; Verbeek, M M; Rostagno, A; Bojsen-Moller, M; David, G; van Horssen, J; Braendgaard, H; Plant, G; Frangione, B; Ghiso, J; Revesz, T
2006 Oct;32(5):492-504, Neuropathology & applied neurobiology
Molecular chaperons or amyloid-associated proteins (AAPs) are deposited in vascular and parenchymal amyloid lesions in Alzheimer's disease (AD) and other amyloidoses. AAPs, such as apolipoprotein E (ApoE) or apolipoprotein J (ApoJ) have been strongly implicated in the pathogenesis of AD in vitro and in vivo. Furthermore the possession of the ApoE in4 allele is a well-studied risk factor for AD. In view of the similarities between AD and both familial British dementia (FBD) and familial Danish dementia (FDD), we investigated the presence of AAPs in these two diseases to understand better their role in the general process of amyloidogenesis. Immunohistochemistry for ApoE, ApoJ, serum amyloid P (SAP), alpha-1-antichymotrypsin, cystatin C, heparan sulphate proteoglycans, such as agrin, perlecan, syndecans, glypican-1 and for heparan sulphate glycosaminoglycan (HS GAG) side chains was carried out together with immunohistochemical preparations specific to the amyloid subunits. Significant or extensive staining for ApoE, ApoJ, agrin, glypican-1 and HS GAG side chains was found in both amyloid (fibrillar) and preamyloid (nonfibrillar) deposits in FBD and FDD. The remaining AAPs, including SAP, were predominantly found in amyloid lesions. Only very weak staining was present in a small proportion of the amyloid lesions using perlecan immunohistochemistry. These findings suggest that the deposition patterns of AAPs in FBD and FDD are mostly similar to those in AD. The presence of AAPs in the preamyloid lesions supports the notion that chaperon molecules may play a role in the early steps of fibrillogenesis
— id: 73959, year: 2006, vol: 32, page: 492, stat: Journal Article,

Plaque-associated overexpression of insulin-degrading enzyme in the cerebral cortex of aged transgenic tg2576 mice with Alzheimer pathology
Leal, Maria C; Dorfman, Veronica B; Gamba, Agata Fernandez; Frangione, Blas; Wisniewski, Thomas; Castano, Eduardo M; Sigurdsson, Einar M; Morelli, Laura
2006 Oct;65(10):976-987, Journal of neuropathology & experimental neurology
It was proposed that insulin-degrading enzyme (IDE) participates in the clearance of amyloid beta (Abeta) in the brain, and its low expression or activity may be relevant for the progression of Alzheimer disease. We performed a longitudinal study of brain level, activity, and distribution of IDE in transgenic mice (Tg2576) expressing the Swedish mutation in human Abeta precursor protein. At 16 months of age, Tg2576 showed a significant 2-fold increment in IDE protein level as compared with 4.5- and 11-month-old animals. The peak of IDE was in synchrony with the sharp accumulation of sodium dodecyl sulfate-soluble Abeta and massive Abeta deposition into plaques. At this stage, IDE appeared surrounding Abeta fibrillar deposits within glial fibrillar acidic protein-positive astrocytes, suggesting that it was locally overexpressed during the Abeta-mediated inflammation process. When primary astrocytes were exposed to fibrillar Abeta in vitro, IDE protein level increased as compared with control, and this effect was reduced by the addition of U0126, a specific inhibitor of the ERK1/2 mitogen-activated protein kinase cascade. We propose that in Tg2576 mice and in contrast to its behavior in Alzheimer brains, active IDE increases with age around plaques as a component of astrocyte activation as a result of Abeta-triggered inflammation
— id: 68945, year: 2006, vol: 65, page: 976, stat: Journal Article,

Studies on the first described Alzheimer's disease amyloid beta mutant, the Dutch variant
Levy, Efrat; Prelli, Frances; Frangione, Blas
2006 ;9(3 Suppl):329-339, Journal of Alzheimer's Disease
Amyloid protein deposited in cerebral vessel walls and diffuse plaques of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), is similar to the 40-42 residues amyloid beta (Abeta) in vessel walls and senile plaques in brains of patients with Alzheimer's disease (AD), Down's syndrome, and familial and sporadic cerebral amyloid angiopathy (CAA). In 1990 we sequenced the amyloid beta-protein precursor (AbetaPP) gene from HCHWA-D patients revealing a single mutation that results in an amino acid substitution, Abeta E22Q. Subsequent identification of additional mutations in the AbetaPP gene in familial AD (FAD) pedigrees revealed that whereas substitutions in the middle of Abeta, residues Abeta21-23, are predominantly vasculotropic, those found amino- or carboxyl-terminal to the Abeta sequence within AbetaPP enhance amyloid parenchymal plaque deposition. Studies of transfected cells showed that substitutions amino- or carboxyl-terminal to Abeta lead to either greater Abeta production or to enhanced secretion of the more hydrophobic thus more fibrillogenic Abeta1-42. Substitutions in the center of Abeta facilitate rapid aggregation and fibrillization, slower clearance across the blood-brain barrier and perivascular drainage to the systemic circulation, possibly higher resistance to proteolysis, and enhanced toxicity towards endothelial and smooth muscle cells. However, most AD patients have no genetic defects in AbetaPP, indicating that other factors may alter Abeta production, conformation, and/or clearance initiating the disease process
— id: 68936, year: 2006, vol: 9, page: 329, stat: Journal Article,

Matrix metalloproteases and A-beta clearance
Tomidokoro Y; Lashley T; Revesz T; Greenberg S; Frangione B; Rostagno A; Ghiso J
2006 ;2(3 Suppl 1):S536-S537, Alzheimer's & Dementia
— id: 73969, year: 2006, vol: 2, page: S536, stat: Journal Article,

BRI2 modulates amyloid precursor protein processing and inhibits A-beta generation
Tsachaki M; Fotinopoulou A; Vlavaki M; Poulopoulos A; Rostagno A; Fragione B; Ghiso J; Efthimiopoulos S
2006 ;2(3 Suppl 1):S36-S36, Alzheimer's & Dementia
— id: 73966, year: 2006, vol: 2, page: S36, stat: Journal Article,

Clusterin and Alzheimer's disease
Calero, Miguel; Rostagno, Agueda; Frangione, Blas; Ghiso, Jorge
2005 ;38:273-298, Sub-cellular biochemistry
Clusterin (apolipoprotein J) is a ubiquitous multifunctional glycoprotein with the capability to interact with a broad spectrum of molecules, among them the Alzheimer's Abeta peptide. Due to its co-localization with fibrillar deposits in systemic and cerebral amyloid disorders, clusterin is also considered an amyloid-associated protein. Although no genuine function has been attributed to this protein so far, it has been implicated in a wide variety of physiological and pathological processes, a role that may vary according to the protein maturation, sub-cellular localization, and the presence of certain tissue- or cell-specific factors. This review focuses on the importance of clusterin in health and disease conditions, with particular emphasis in its role in Abeta amyloidosis and other disorders of protein folding
— id: 56305, year: 2005, vol: 38, page: 273, stat: Journal Article,

BRI2 interacts with APP and regulates Abeta production
Fotinopoulou, Angeliki; Tsachaki, Maria; Vlavaki, Maria; Poulopoulos, Alexandros; Rostagno, Agueda; Frangione, Blas; Ghiso, Jorge; Efthimiopoulos, Spiros
2005 Sep;280(35):30768-30772, Journal of biological chemistry
Transmembrane proteins BRI2 and APP co-localize with Ass amyloid lesions in sporadic Alzheimer's disease and mutations in both precursor proteins are linked to early-onset familial cases of cerebral amyloidosis associated with dementia and/or cerebral haemorrhage. A specific interaction between BRI2 and APP was unveiled by immunoprecipitation experiments using transfected and non-transfected cells. The use of deletion mutants further revealed that stretches 648-719 of APP751 and 46-106 of BRI2, both inclusive of the full transmembrane domains, are sufficient for the interaction. Removal of most of the APP and BRI2 extracellular domains without affecting the interaction implies that both proteins interact when are expressed on the same cell membrane (cis) rather than on adjacent cells (trans). The presence of BRI2 had a modulatory effect on APP processing, specifically increasing the levels of cellular APP as well as ss-secretase-generated C-terminal fragments while decreasing the levels of a-secretase-generated C-terminal fragments as well as the secretion of total APP and Ass peptides. Determining the precise molecular pathways affected by the specific binding between APP and BRI2 could result in the identification of common therapeutic targets for these sporadic and familial neurodegenerative disorders
— id: 56303, year: 2005, vol: 280, page: 30768, stat: Journal Article,

Familial British and Danish dementias
Ghiso J; Rostagno A; Tomidokoro Y; Lashley T; Holton J; Plant G; Revesz T; Frangione B
Amyloid proteins : the beta sheet conformation and disease Weinheim : Wiley-VCH, 2005,
— id: 5113, year: 2005, vol: , page: 515, stat: Chapter,

Amyloid-associated proteins (AAPs) in familial British dementia (FBD) and familial Danish dementia (FDD)
Lashley, T; Holton, JL; Frangione, B; van Horssen, J; Rostagno, A; Verbeek, MM; Ghiso, J; Revesz, T
2005 APR ;31(2):244-244, Neuropathology & applied neurobiology
— id: 73960, year: 2005, vol: 31, page: 244, stat: Journal Article,

The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production
Matsuda, Shuji; Giliberto, Luca; Matsuda, Yukiko; Davies, Peter; McGowan, Eileen; Pickford, Fiona; Ghiso, Jorge; Frangione, Blas; D'Adamio, Luciano
2005 Aug 12;280(32):28912-28916, Journal of biological chemistry
Alzheimer disease (AD), the most common senile dementia, is characterized by amyloid plaques, vascular amyloid, neurofibrillary tangles, and progressive neurodegeneration. Amyloid is mainly composed by amyloid-beta (A(beta)) peptides, which are derive from processing of the beta-amyloid precursor protein (APP), better named amyloid-beta precursor protein (A(beta)PP), by secretases. The A(beta)PP intracellular domain (AID), which is released together with A(beta), has signaling function, since it modulates apoptosis and transcription. Despite its biological and pathological importance, the mechanisms regulating A(beta)PP processing are poorly understood. As cleavage of other gamma-secretase substrates is regulated by membrane bound proteins, we have postulated the existence of integral membrane proteins that bind A(beta)PP and regulate its processing. Here, we show that BRI2, a type II membrane protein, interacts with A(beta)PP. Interestingly, 17 amino acids corresponding to the NH2-terminal portion of A(beta) are necessary for this interaction. Moreover, BRI2 expression regulates A(beta)PP processing resulting in reduced A(beta) and AID levels. Altogether, these findings characterize the BRI2-A(beta)PP interaction as a regulatory mechanism of A(beta)PP processing that inhibits A(beta) production. Notably, BRI2 mutations cause familial British (FBD) and Danish dementias (FDD) that are clinically and pathologically similar to AD. Finding that BRI2 pathogenic mutations alter the regulatory function of BRI2 on A(beta)PP processing would define dysregulation of A(beta)PP cleavage as a pathogenic mechanism common to AD, FDD, and FBD
— id: 81095, year: 2005, vol: 280, page: 28912, stat: Journal Article,

Insulin-degrading enzyme degrades amyloid peptides associated with British and Danish familial dementia
Morelli, Laura; Llovera, Ramiro E; Alonso, Leonardo G; Frangione, Blas; de Prat-Gay, Gonzalo; Ghiso, Jorge; Castano, Eduardo M
2005 Jul 8;332(3):808-816, Biochemical & biophysical research communications
Familial British dementia (FBD) and familial Danish dementia (FDD) are autosomal dominant disorders characterized by cerebrovascular and parenchymal amyloid deposition and neurofibrillary degeneration. In both conditions, the genetic defects cause the loss of the normal stop codon in the precursor BRI, generating novel 34-residue peptides named ABri and ADan in FBD and FDD, respectively. ABri and ADan show a strong tendency to aggregate into non-fibrillar and fibrillar structures at neutral pH and this property seems to be directly related to neurotoxicity. Here we report that a recombinant insulin-degrading enzyme (rIDE) was capable of degrading monomeric ABri and ADan in vitro more efficiently than oligomeric species. These peptides showed high beta-structure content and were more resistant to proteolysis as compared to the BRI wild-type product of 23 amino acids. Specific sites of cleavage within the C-terminal pathogenic extensions raise the possibility that proteolysis of monomeric soluble precursors by IDE may delay ABri and ADan aggregation in vivo
— id: 81097, year: 2005, vol: 332, page: 808, stat: Journal Article,

Purification of human wild-type or variant cystatin C from conditioned media of transfected cells
Prelli, Frances; Pawlik, Monika; Frangione, Blas; Levy, Efrat
2005 ;299:221-226, Methods in molecular biology
The characterization of proteins in their native state is essential for the understanding of patho-genic isoforms. A variant of the cysteine protease inhibitor cystatin C is the major constituent of the amyloid deposited in the cerebral vasculature of patients with the Icelandic form of hereditary cerebral hemorrhage with amyloidosis (HCHWA-I). In order to study the nature of the bio-physical changes owing to the Leu68Gln substitution in cystatin C, we have developed a purification procedure of human cystatin C in its native state. The protein is isolated from media of stably transfected tissue culture cells using physiological conditions that preclude protein denaturation. The importance of mild purification conditions is underscored by the finding that denaturation of the wild-type and variant proteins facilitates a similar folding of both molecules, diminishing their differences in structure and biophysical properties. Following native purification conditions, variant cystatin C has a distinct structure compared to the wild-type protein
— id: 56366, year: 2005, vol: 299, page: 221, stat: Journal Article,

Amyloid ion channels: a common structural link for protein-misfolding disease
Quist, Arjan; Doudevski, Ivo; Lin, Hai; Azimova, Rushana; Ng, Douglas; Frangione, Blas; Kagan, Bruce; Ghiso, Jorge; Lal, Ratnesh
2005 Jul 26;102(30):10427-10432, Proceedings of the National Academy of Sciences of the United States of America
Protein conformational diseases, including Alzheimer's, Huntington's, and Parkinson's diseases, result from protein misfolding, giving a distinct fibrillar feature termed amyloid. Recent studies show that only the globular (not fibrillar) conformation of amyloid proteins is sufficient to induce cellular pathophysiology. However, the 3D structural conformations of these globular structures, a key missing link in designing effective prevention and treatment, remain undefined as of yet. By using atomic force microscopy, circular dichroism, gel electrophoresis, and electrophysiological recordings, we show here that an array of amyloid molecules, including amyloid-beta(1-40), alpha-synuclein, ABri, ADan, serum amyloid A, and amylin undergo supramolecular conformational change. In reconstituted membranes, they form morphologically compatible ion-channel-like structures and elicit single ion-channel currents. These ion channels would destabilize cellular ionic homeostasis and hence induce cell pathophysiology and degeneration in amyloid diseases
— id: 81094, year: 2005, vol: 102, page: 10427, stat: Journal Article,

Diversity of senile plaques in Alzheimer's disease as revealed by a new monoclonal antibody that recognizes an internal sequence of the Abeta peptide
Rabano, Alberto; Jimenez-Huete, Adolfo; Acevedo, Boris; Calero, Miguel; Ghiso, Jorge; Valdes, Israel; Gavilondo, Jorge; Frangione, Blas; Mendez, Enrique
2005 Oct;2(4):409-417, Current Alzheimer research
In order to have more specific tools available to approach amyloidogenesis in Alzheimer's disease (AD), we have produced several polyclonal and monoclonal antibodies that recognize specific sequences of the amyloid beta (Abeta) peptide. Here we present results that demonstrate that our monoclonal antibody EM5 recognizes an internal sequence (residues 11-16) of the Abeta peptide. This strategic localization of the epitope allowed us to employ this antibody, together with two previously reported polyclonal antibodies (EM2 and EM3, specific for AbetaX-40 and AbetaX-42, respectively), in an immunohistochemical study aimed at exploring the differential distribution of longer (AbetaX-40/42) and shorter (Abeta17-X) peptides along the various types of amyloid deposits of AD. This antibody panel was used in six AD brains, on sections from associative neocortex, striatum and cerebellar cortex. Single and double immunostaining revealed specific staining of vascular amyloid deposits and neuritic plaques by EM5 antibody, with high co-localization of EM2. Our results suggest that EM5 antibody recognizes pathogenic forms of Abeta deposits (amyloid angiopathy and neuritic plaques) and reveals the existence of a subset of plaques with a profile similar to vascular deposits. Additionally, our results show that diffuse plaques in AD brains may contain Abeta17-X peptides as its principal component. EM5 may be a useful tool in research both on human and transgenic mice tissue that may aid in the study of molecular heterogeneity of plaques in AD
— id: 81092, year: 2005, vol: 2, page: 409, stat: Journal Article,

Cerebral amyloid angiopathy
Revesz T; Ghiso J; Plant G; Lashley T; Rostagno A; Frangione B; Holton JL
Cerebrovascular diseases Basel, Switzerland : ISN Neuropath Press, 2005,
— id: 5114, year: 2005, vol: , page: 94, stat: Chapter,

Chromosome 13 dementias
Rostagno, A; Tomidokoro, Y; Lashley, T; Ng, D; Plant, G; Holton, J; Frangione, B; Revesz, T; Ghiso, J
2005 Aug;62(16):1814-1825, Cellular & molecular life sciences: CMLS
The importance of cerebral amyloid deposition in the mechanism of neurodegeneration is still debatable. Classic arguments are usually centered on amyloid beta(Abeta) and its role in the neuronal loss characteristic of Alzheimer's disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias (FBD and FDD), share many aspects of Alzheimer's disease, including the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy and a variety of amyloid-associated proteins and inflammatory components. Both early-onset conditions are linked to specific mutations at or near the stop codon of the chromosome 13 gene BRI2 that cause generation of longer-than-normal protein products. Furin-like processing of these longer precursors releases two de novo-created peptides, ABri and ADan, which deposit as amyloid fibrils in FBD and FDD, respectively. Due to the similar pathology generated by completely unrelated amyloid subunits, FBD and FDD, collectively referred to as chromosome 13 dementias, constitute alternative models for studying the role of amyloid deposition in the mechanism of neuronal cell death
— id: 56304, year: 2005, vol: 62, page: 1814, stat: Journal Article,

Familial Danish dementia: co-existence of Danish and Alzheimer amyloid subunits (ADan AND A{beta}) in the absence of compact plaques
Tomidokoro, Yasushi; Lashley, Tammaryn; Rostagno, Agueda; Neubert, Thomas A; Bojsen-Moller, Marie; Braendgaard, Hans; Plant, Gordon; Holton, Janice; Frangione, Blas; Revesz, Tamas; Ghiso, Jorge
2005 Nov 4;280(44):36883-36894, Journal of biological chemistry
Familial Danish dementia is an early onset autosomal dominant neurodegenerative disorder linked to a genetic defect in the BRI2 gene and clinically characterized by dementia and ataxia. Cerebral amyloid and preamyloid deposits of two unrelated molecules (Danish amyloid (ADan) and beta-amyloid (Abeta)), the absence of compact plaques, and neurofibrillary degeneration indistinguishable from that observed in Alzheimer disease (AD) are the main neuropathological features of the disease. Biochemical analysis of extracted amyloid and preamyloid species indicates that as the solubility of the deposits decreases, the heterogeneity and complexity of the extracted peptides exponentially increase. Nonfibrillar deposits were mainly composed of intact ADan-(1-34) and its N-terminally modified (pyroglutamate) counterpart together with Abeta-(1-42) and Abeta-(4-42) in approximately 1:1 mixture. The post-translational modification, glutamate to pyroglutamate, was not present in soluble circulating ADan. In the amyloid fractions, ADan was heavily oligomerized and highly heterogeneous at the N and C terminus, and, when intact, its N terminus was post-translationally modified (pyroglutamate), whereas Abeta was mainly Abeta-(4-42). In all cases, the presence of Abeta-(X-40) was negligible, a surprising finding in view of the prevalence of Abeta40 in vascular deposits observed in sporadic and familial AD, Down syndrome, and normal aging. Whether the presence of the two amyloid subunits is imperative for the disease phenotype or just reflects a conformational mimicry remains to be elucidated; nonetheless, a specific interaction between ADan oligomers and Abeta molecules was demonstrated in vitro by ligand blot analysis using synthetic peptides. The absence of compact plaques in the presence of extensive neuro fibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia
— id: 61252, year: 2005, vol: 280, page: 36883, stat: Journal Article,

Amyloid: toward terminology clarification. Report from the Nomenclature Committee of the International Society of Amyloidosis
Westermark, Per; Benson, Merrill D; Buxbaum, Joel N; Cohen, Alan S; Frangione, Blas; Ikeda, Shu-Ichi; Masters, Colin L; Merlini, Giampaolo; Saraiva, Maria J; Sipe, Jean D
2005 Mar;12(1):1-4, Amyloid
The modern nomenclature of amyloidosis now includes 25 human and 8 animal fibril proteins. To be included in the list, the protein has to be a major fibril protein in extracellular deposits, which have the characteristics of amyloid, including affinity for Congo red with resulting green birefringence. Synthetic fibrils with amyloid properties are best named 'amyloid-like'. With increasing knowledge, however, the borders between different protein aggregates tend to become less sharp
— id: 96090, year: 2005, vol: 12, page: 1, stat: Journal Article,

Immunological and anti-chaperone therapeutic approaches for Alzheimer disease
Wisniewski, Thomas; Frangione, Blas
2005 Jan;15(1):72-77, Brain pathology
Alzheimer disease (AD) is the most common cause of dementia. Currently available therapies only provide symptomatic relief. A number of therapeutic approaches are under development that aim to increase the clearance of brain Abeta peptides. These include immune mediated clearance of Abeta and the inhibition of the interaction between Abeta and its pathological chaperones. Both active and passive immunization has been shown to have robust effects in transgenic mouse models of AD on amyloid reduction and behavioral improvements. However, a human trial of active immunization has been associated with significant toxicity in a minority of patients. New generation vaccines are being developed which likely will reduce the potential for cell-mediated toxicity. In addition, the recent development of anti-chaperone therapy opens a new therapeutic avenue which is unlikely to be associated with toxicity
— id: 51394, year: 2005, vol: 15, page: 72, stat: Journal Article,

Antibody mediated modulation of A beta induced neurotoxicity in cell culture
Asuni, AA; Knudsen, E; Frangione, B; Wisniewski, T; Sigurdsson, EM
2004 JUL ;25(10):S581-S582, Neurobiology of aging
— id: 47745, year: 2004, vol: 25, page: S581, stat: Journal Article,

Purification, characterization, and immunolocalization of paramyosin from the adult stage of Fasciola hepatica
Cancela, Martin; Carmona, Carlos; Rossi, Silvina; Frangione, Blas; Goni, Fernando; Berasain, Patricia
2004 Apr;92(6):441-448, Parasitology research
Paramyosin, a vaccine candidate in different helminthiases, was purified from the adult liver fluke Fasciola hepatica using two different procedures. The first started with a crude extraction of paramyosin in high-salt buffer followed by gel filtration chromatography and two precipitation-solubilization cycles; in the second, anion exchange chromatography replaced the gel filtration step. In both cases, the apparent molecular weight of the purified protein determined by sodium dodecyl sulfate gel electrophoresis under reducing and non-reducing conditions was 97 kDa and 200 kDa, respectively. The molecular weights were consistent with the presence of a dimeric protein linked by disulfide bridges. Western blot analysis showed that the dimeric and monomeric forms were both recognized by an antiserum raised against the F. hepatica 97 kDa band (alpha-FhPmy), and by an anti- Schistosoma mansoni paramyosin immune serum. Immunohistochemistry using alpha-FhPmy demonstrated the localization of paramyosin within the subtegumental muscle and in muscle cells surrounding the gut of adult parasites. We also observed labeling of extramuscular structures like testes, surface lamellae of the gut and the tegument of adult flukes
— id: 101672, year: 2004, vol: 92, page: 441, stat: Journal Article,

Axonal transport of British and Danish amyloid peptides via secretory vesicles
Choi, Seung-Il; Vidal, Ruben; Frangione, Blas; Levy, Efrat
2004 Feb;18(2):373-375, FASEB journal
The ABri and ADan amyloid peptides deposited in familial British and Danish neurodegenerative disorders are generated by processing mutant forms of the precursor protein BRI2. Although the pathogenic process that leads to deposition of amyloid in the brains of patients has been studied extensively, the cellular processes and normal function of the precursor protein did not receive much attention. We observed in a variety of transfected cell lines the presence of two independent proteolytic processing events. In addition to the previously described cleavage, which results in the production of carboxyl-terminal approximately 3 kDa wild-type peptide or approximately 4 kDa ABri or ADan peptides, we describe a novel amino-terminal cleavage site within BRI2. Both cleavages occur within the cis- or medial-Golgi. Following cleavage, the BRI2-derived carboxyl-terminal peptides are transported via a regulated secretory pathway into secretory vesicles in neuronal cells. Worth noting is that expression of wild-type British or Danish mutants of BRI2, in mouse neuroblastoma N2a cells that do not express endogenous BRI2, induces elongation of neurites, which suggests a role for this protein in differentiation of neuronal cells
— id: 42639, year: 2004, vol: 18, page: 373, stat: Journal Article,

Synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid beta for induction of an immune response to amyloid beta and amyloid deposits
Frangione, Blas; Wisniewski, Thomas; Sigurdsson, Einar M
2004 ;1280(5):S30-S31, Official gazette of the United States Patent & Trademark Office. Patents
The present invention relates to synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid beta which can be used alone or conjugated to an immunostimulatory molecule in an immunizing composition for inducing an immune response to amyloid beta peptides and amyloid deposits
— id: 97981, year: 2004, vol: 1280, page: S30, stat: Journal Article,

Systemic catabolism of Alzheimer's Abeta40 and Abeta42
Ghiso, Jorge; Shayo, Marcos; Calero, Miguel; Ng, Douglas; Tomidokoro, Yasushi; Gandy, Samuel; Rostagno, Agueda; Frangione, Blas
2004 Oct 29;279(44):45897-45908, Journal of biological chemistry
To better understand the physiologic excretion and/or catabolism of circulating peripheral amyloid beta (Abeta), we labeled human Abeta40 (monomeric, with predominant unordered structure) and Abeta42 (mixture of monomers and oligomers in approximately 50:50 ratio, rich in beta-sheet conformation) with either Na(125)I or (125)I-tyramine cellobiose, also known as the cell-trapping ligand procedure, testing their blood clearance and organ uptake in B6SJLF1/J mice. Irrespective of the labeling protocol, the peptide conformation, and the degree of oligomerization, both Abeta40 and Abeta42 showed a short half-life of 2.5-3.0 min. The liver was the major organ responsible for plasma clearance, accounting for >60% of the peptide uptake, followed by the kidney. In vivo, hepatocytes captured >90% of the radiolabeled peptides which, after endocytosis, were preferentially catabolized and excreted into the bile. Biliary excretion of intact as well as partially degraded Abeta species became obviously relevant at doses above 10 microg. The use of biotin-labeled Abeta allowed the visualization of the interaction with HepG2 cells in culture, whereas competitive inhibition experiments with unlabeled Abeta demonstrated the specificity of the binding. The capability of the liver to uptake, catabolize, and excrete large doses of Abeta, several orders of magnitude above its physiologic concentration, may explain not only the femtomolar plasma levels of Abeta but the little fluctuation observed with age and disease stages
— id: 47833, year: 2004, vol: 279, page: 45897, stat: Journal Article,

The possible origin of the amyloid peptides in the BRI2 gene-related dementias
Lashley, T; Holton, JL; Frangione, B; Bandopadhyay, R; Ghiso, J; Rostagno, A; Revesz, T
2004 JUL ;25(10):S171-S171, Neurobiology of aging
— id: 47722, year: 2004, vol: 25, page: S171, stat: Journal Article,

Soluble Abeta homeostasis in AD and DS: impairment of anti-amyloidogenic protection by lipoproteins
Matsubara, Etsuro; Sekijima, Yoshiki; Tokuda, Takahiko; Urakami, Katsuya; Amari, Masakuni; Shizuka-Ikeda, Masami; Tomidokoro, Yasushi; Ikeda, Masaki; Kawarabayashi, Takeshi; Harigaya, Yasuo; Ikeda, Shu-ichi; Murakami, Tetsuro; Abe, Koji; Otomo, Eiichi; Hirai, Shunsaku; Frangione, Blas; Ghiso, Jorge; Shoji, Mikio
2004 Aug;25(7):833-841, Neurobiology of aging
In order to assess whether lipoproteins are physiologically able to balance and modulate the sAbeta homeostasis in vivo, soluble Abeta levels in lipoprotein-depleted plasma were measured as a function of age in normal controls, Alzheimer's disease (AD) patients, and Down's syndrome (DS) cases. The reshaping of sAbeta homeostasis, in particular the sAbeta42-lipoprotein interaction, takes place over normal-60's, whereas mild AD patients appear to have impaired this anti-amyloidogenic mechanism resulting in a significant increase of lipoprotein-free sAbeta42. Similar loss of function takes place in Down's syndrome patients. Lipoprotein-free sAbeta remains significantly elevated from the pre-symptomatic through the symptomatic stages of the disease, and declines with the progression of the AD-like pathology. The dissociation of sAbeta from lipoprotein-particles also occurs in brain parenchyma and the presence of soluble dimeric lipoprotein-free Abeta prior to its parenchymal deposition in AD brains would support the hypothesis that functionally declined lipoproteins may be major determinants in the production of metabolic conditions leading to higher levels of sAbeta species and cerebral amyloidosis
— id: 81099, year: 2004, vol: 25, page: 833, stat: Journal Article,

Insulin degrading enzyme from human brain microvessels degrades amyloid beta and its Flemish, Dutch and Italian vasculotropic variants
Morelli, L; Llovera, RE; Frangione, B; Ghiso, J; Castano, EM
2004 JUL ;25(10):S146-S146, Neurobiology of aging
— id: 47720, year: 2004, vol: 25, page: S146, stat: Journal Article,

Insulin-degrading enzyme in brain microvessels: proteolysis of amyloid {beta} vasculotropic variants and reduced activity in cerebral amyloid angiopathy
Morelli, Laura; Llovera, Ramiro E; Mathov, Irina; Lue, Lih-Fen; Frangione, Blas; Ghiso, Jorge; Castano, Eduardo M
2004 Dec 31;279(53):56004-56013, Journal of biological chemistry
The accumulation of amyloid beta (Abeta) in the walls of small vessels in the cerebral cortex is associated with diseases characterized by dementia or stroke. These include Alzheimer's disease, Down syndrome, and sporadic and hereditary cerebral amyloid angiopathies (CAAs) related to mutations within the Abeta sequence. A higher tendency of Abeta to aggregate, a defective clearance to the systemic circulation, and insufficient proteolytic removal have been proposed as mechanisms that lead to Abeta accumulation in the brain. By using immunoprecipitation and mass spectrometry, we show that insulin-degrading enzyme (IDE) from isolated human brain microvessels was capable of degrading (125)I-insulin and cleaved Abeta-(1-40) wild type and the genetic variants Abeta A21G (Flemish), Abeta E22Q (Dutch), and Abeta E22K (Italian) at the predicted sites. In microvessels from Alzheimer's disease cases with CAA, IDE protein levels showed a 44% increase as determined by sandwich enzyme-linked immunosorbent assay and Western blot. However, the activity of IDE upon radiolabeled insulin was significantly reduced in CAA as compared with age-matched controls. These results support the notion that a defect in Abeta proteolysis by IDE contributes to the accumulation of this peptide in the cortical microvasculature. Moreover they raise the possibility that IDE inhibition or inactivation is a pathogenic mechanism that may open novel strategies for the treatment of cerebrovascular Abeta amyloidoses
— id: 81098, year: 2004, vol: 279, page: 56004, stat: Journal Article,

Familial and sporadic cerebral amyloid angiopathies associated with dementia and the BRI dementias
Plant, Gordon T; Revesz, Tamas; Holton, Janice L; Ghiso, Jorge; Frangione, Blas
The neuropathology of dementia Cambridge UK : Cambridge University Press, 2004,
— id: 4822, year: 2004, vol: , page: ?, stat: Chapter,

Familial British and Danish dementias: BRI2 gene and protein expression by human cerebral cells
Rostagno, A; Zhao, ZH; Ng, D; Lashley, T; Holton, J; Frangione, B; Revesz, T; Ghiso, J
2004 JUL ;25(10):S170-S171, Neurobiology of aging
— id: 47721, year: 2004, vol: 25, page: S170, stat: Journal Article,

Binding of cystatin C to Alzheimer's amyloid beta inhibits in vitro amyloid fibril formation
Sastre, Magdalena; Calero, Miguel; Pawlik, Monika; Mathews, Paul M; Kumar, Asok; Danilov, Vlatko; Schmidt, Stephen D; Nixon, Ralph A; Frangione, Blas; Levy, Efrat
2004 Oct;25(8):1033-1043, Neurobiology of aging
The colocalization of cystatin C, an inhibitor of cysteine proteases, with amyloid beta (Abeta) in parenchymal and vascular amyloid deposits in brains of Alzheimer's disease (AD) patients may reflect cystatin C involvement in amyloidogenesis. We therefore sought to determine the association of cystatin C with Abeta. Immunofluorescence analysis of transfected cultured cells demonstrated colocalization of cystatin C and beta amyloid precursor protein (betaAPP) intracellularly and on the cell surface. Western blot analysis of immunoprecipitated cell lysate or medium proteins revealed binding of cystatin C to full-length betaAPP and to secreted betaAPP (sbetaAPP). Deletion mutants of betaAPP localized the cystatin C binding site within betaAPP to the Abeta region. Cystatin C association with betaAPP resulted in increased sbetaAPP but did not affect levels of secreted Abeta. Analysis of the association of cystatin C and Abeta demonstrated a specific, saturable and high affinity binding between cystatin C and both Abeta(1-42) and Abeta(1-40). Notably, cystatin C association with Abeta results in a concentration-dependent inhibition of Abeta fibril formation
— id: 46126, year: 2004, vol: 25, page: 1033, stat: Journal Article,

An attenuated immune response is sufficient to enhance cognition in an Alzheimer's disease mouse model immunized with amyloid-beta derivatives
Sigurdsson, Einar M; Knudsen, Elin; Asuni, Ayodeji; Fitzer-Attas, Cheryl; Sage, Daniel; Quartermain, David; Goni, Fernando; Frangione, Blas; Wisniewski, Thomas
2004 Jul 14;24(28):6277-6282, Journal of neuroscience
Immunization with amyloid-beta (Abeta) 1-42 has been shown to reduce amyloid burden and improve cognition in Alzheimer's disease (AD) model mice. In a human trial, possible cognitive benefit was found but in association with significant toxicity in a minority of patients. We proposed that immunization with nonfibrillogenic Abeta derivatives is much less likely to produce toxicity and have previously shown that one such derivative (K6Abeta1-30) can reduce amyloid burden in mice to a similar extent as Abeta1-42. Here, we immunized AD model mice (Tg2576) with Abeta1-30[E18E19] or with K6Abeta1-30[E18E19]. These peptides were designed to be nontoxic and to produce less T-cell response, which has been linked to toxicity. K6Abeta1-30[E18E19] induced primarily an IgM response, whereas Abeta1-30[E18E19] induced an IgG titer that was lower than previously seen with K6Abeta1-30 or Abeta1-42. However, both treated animal groups performed better than Tg controls in the radial arm maze. Amyloid burden was similar in Abeta1-30[E18E19]-vaccinated mice and their Tg controls, whereas the number of medium and small sized plaques was reduced (29-34%) in K6Abeta1-30[E18E19]-immunized mice compared with Tg controls. Amyloid burden in these mice correlated inversely with plasma IgM levels. The cognitive benefit and amyloid reduction in the K6Abeta1-30[E18E19]-vaccinated mice are likely to be related to peripheral clearance of Abeta, because IgM does not cross the blood-brain barrier because of its large size. Our results indicate that these nontoxic Abeta derivatives produce an attenuated antibody response, which is less likely to be associated with negative side effects while having cognitive benefits
— id: 44513, year: 2004, vol: 24, page: 6277, stat: Journal Article,

Modest immune response elicited by A beta derivatives in TG2576 mice improves cognition
Sigurdsson, EM; Knudsen, E; Asuni, A; Sage, D; Goni, F; Quartermam, D; Frangione, B; Wisniewski, T
2004 JUL ;25(10):S576-S576, Neurobiology of aging
— id: 47744, year: 2004, vol: 25, page: S576, stat: Journal Article,

Biochemical analysis of A beta amyloid deposits in the Iowa variant of Alzheimer's disease
Tomidokoro, Y; Rostagno, A; Greenberg, SM; Frangione, B; Rebeck, WG; Ghiso, J
2004 JUL ;25(10):S38-S38, Neurobiology of aging
— id: 47713, year: 2004, vol: 25, page: S38, stat: Journal Article,

Imaging and therapeutic approaches for beta-sheet structures in prion and Alzheimer's diseases
Wisniewski, T; Pankiewicz, J; Scholtzova, H; Fernando, G; Chabalgoity, JA; Ji, Y; Wadghiri, YZ; Gan, WB; Tang, CY; Turnbull, DH; Mathis, CA; Kascsak, R; Klunk, WE; Carp, RI; Frangione, B; Sigurdsson, EM; Sadowski, M
2004 ;25(2):S30-S31, Neurobiology of aging
— id: 97595, year: 2004, vol: 25, page: S30, stat: Journal Article,

Identification of distinct N-terminal truncated forms of prion protein in different Creutzfeldt-Jakob disease subtypes
Zanusso, Gianluigi; Farinazzo, Alessia; Prelli, Frances; Fiorini, Michele; Gelati, Matteo; Ferrari, Sergio; Righetti, Pier Giorgio; Rizzuto, Nicolo; Frangione, Blas; Monaco, Salvatore
2004 Sep 10;279(37):38936-38942, Journal of biological chemistry
In prion diseases, the cellular prion protein (PrP(C)) is converted to an insoluble and protease-resistant abnormal isoform termed PrP(Sc). In different prion strains, PrP(Sc) shows distinct sites of endogenous or exogenous proteolysis generating a core fragment named PrP27-30. Sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disease, clinically presents with a variety of neurological signs. As yet, the clinical variability observed in sCJD has not been fully explained by molecular studies relating two major types of PrP27-30 with unglycosylated peptides of 21 (type 1) and 19 kDa (type 2) and the amino acid methionine or valine at position 129. Recently, smaller C-terminal fragments migrating at 12 and 13 kDa have been detected in different sCJD phenotypes, but their significance remains unclear. By using two-dimensional immunoblot with anti-PrP antibodies, we identified two novel groups of protease-resistant PrP fragments in sCJD brain tissues. All sCJD cases with type 1 PrP27-30, in addition to MM subjects with type 2 PrP27-30, were characterized by the presence of unglycosylated PrP fragments of 16-17 kDa. Conversely, brain homogenates from patients VV and MV with type 2 PrP27-30 contained fully glycosylated PrP fragments, which after deglycosylation migrated at 17.5-18 kDa. Interestingly, PrP species of 17.5-18 kDa matched deglycosylated forms of the C1 PrP(C) fragment and were associated with tissue PrP deposition as plaque-like aggregates or amyloid plaques. These data show the presence of multiple PrP(Sc) conformations in sCJD and, in addition, shed new light on the correlation between sCJD phenotypes and disease-associated PrP molecules
— id: 101671, year: 2004, vol: 279, page: 38936, stat: Journal Article,

SiRNA-mediated BRI2 gene silencing in human neuronal cells
Zhao, ZH; Rostagno, A; Revesz, T; Frangione, B; Ghiso, J
2004 JUL ;25(10):S470-S471, Neurobiology of aging
— id: 47742, year: 2004, vol: 25, page: S470, stat: Journal Article,

Specific cleavage sites on human IgG subclasses by cruzipain, the major cysteine proteinase from Trypanosoma cruzi
Berasain, Patricia; Carmona, Carlos; Frangione, Blas; Cazzulo, Juan Jose; Goni, Fernando
2003 Aug 11;130(1):23-29, Molecular & biochemical parasitology
Cruzipain, the major cysteine proteinase of Trypanosoma cruzi, might have other biological roles than its metabolic functions. In this report, we have explored the interaction of cruzipain with molecules of the immune system. The enzyme was used to digest all human IgG subclasses at different pH values and lengths of time. At pH 7.3, all subclasses were readily split at the hinge region. Immunoblot and amino acid sequence analysis showed fragments of IgG1 and IgG3 to be compatible with Fab and Fc, whereas IgG2 and IgG4 rendered Fab2 and Fc. In all cases the fragments produced might impair the binding capacities and the effector functions of specific IgG. At these cleavage sites cruzipain displays cathepsin L and/or cathepsin B activities and shows a clear preference for Pro at the P'2 position and polar residues at P1. Despite the activity of cruzipain within the hinge, the enzyme also cleaved all heavy chains between the CH2 and CH3 domains; producing Fc'-like-fragments of 14 kDa. These fragments are potential candidates to block or saturate Fc receptors on immunocompetent cells. At mild acidic pH cruzipain produced further degradation of the Fc of all subclasses, the Fd of IgG4 and partially the Fd of IgG1, with the consistent loss of any antibody activity. The L chains apparently were not affected. Thus, cruzipain should be able to modulate, depending on the subclass selected and the pH of the environment, the production and the length of different biologically active/inactive IgG fragments
— id: 101673, year: 2003, vol: 130, page: 23, stat: Journal Article,

Axonal transport of British and Danish amyloid peptides via secretory vesicles
Choi, SI; Vidal, R; Frangione, B; Levy, E
2003 DEC ;17(15):275-281, FASEB journal
The ABri and ADan amyloid peptides deposited in familial British and Danish neurodegenerative disorders are generated by processing mutant forms of the precursor protein BRI2. Although the pathogenic process that leads to deposition of amyloid in the brains of patients has been studied extensively, the cellular processes and normal function of the precursor protein did not receive much attention. We observed in a variety of transfected cell lines the presence of two independent proteolytic processing events. In addition to the previously described cleavage, which results in the production of carb oxyl-terminal similar to3 kDa wild-type peptide or similar to4 kDa ABri or ADan peptides, we describe a novel amino-terminal cleavage site within BRI2. Both cleavages occur within the cis- or medial-Golgi. Following cleavage, the BRI2-derived carb oxyl-terminal peptides are transported via a regulated secretory pathway into secretory vesicles in neuronal cells. Worth noting is that expression of wild-type British or Danish mutants of BRI2, in mouse neuroblastoma N2a cells that do not express endogenous BRI2, induces elongation of neurites, which suggests a role for this protein in differentiation of neuronal cells
— id: 42536, year: 2003, vol: 17, page: 275, stat: Journal Article,

RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain
Deane, Rashid; Du Yan, Shi; Submamaryan, Ram Kumar; LaRue, Barbara; Jovanovic, Suzana; Hogg, Elizabeth; Welch, Deborah; Manness, Lawrence; Lin, Chang; Yu, Jin; Zhu, Hong; Ghiso, Jorge; Frangione, Blas; Stern, Alan; Schmidt, Ann Marie; Armstrong, Don L; Arnold, Bernd; Liliensiek, Birgit; Nawroth, Peter; Hofman, Florence; Kindy, Mark; Stern, David; Zlokovic, Berislav
2003 Jul;9(7):907-913, Nature medicine
Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis
— id: 42003, year: 2003, vol: 9, page: 907, stat: Journal Article,

Familial and sporadic cerebral amyloid angiopathies
Fragione B; Prelli F; Ghiso J; Revesz T
Third International Congress on Vascular Dementia : Prague, Czech Republic, October 23-26, 2003 Bologna : Monduzzi Editore, 2003,
— id: 5153, year: 2003, vol: , page: 35, stat: Chapter,

Immunization with amyloid - beta derivatives improves cognition while provoking a weak antibody response
Knudsen, E. L.; Wisniewski, T.; Quartermain, D.; Sage, D.; Scholtzova, H.; Frangione, B.; Sigurdsson, E. M.
2003 ;2003(5):Abstract No. 133.10-S31, Society for Neuroscience Abstract Viewer & Itinerary Planner
We have reported that an amyloid-beta derivative, K6Abeta1-30-NH2 reduces amyloid burden in mice to a similar extent as previously shown for Abeta1-42 (Am J Pathol 159:439-47,2001). This derivative may be a safer alternative to Alzheimer's vaccination with Abeta1-42 because it has a low beta-sheet content while maintaining the main antigenic sites of Abeta. To determine the in vivo effect of other derivatives with similar in vitro properties, we immunized Tg2576 mice with Abeta1-30-NH2, in which amino acids 18 and 19 were substituted with glutamate (Abeta1-30E18E19). In a parallel study, mice were immunized with K6Abeta1-30E18E19. Freund's adjuvant was used to allow a comparison with our findings with K6Abeta1-30-NH2. Antibody titers were detectable, but much lower than we had observed for K6Abeta1-30-NH2 or Abeta1-42, indicating that the central hydrophobic region of Abeta may have an epitope important for modulating humoral response. Cognitive performance was assessed in a radial arm maze before sacrifice at 19-21 months. Control Tg mice had more errors than their wild-type littermates (p<0.01), and the Abeta1-30E18E19-treated mice (p<0.05). Mice receiving K6Abeta1-30E18E19 also performed better than their Tg controls (p<0.05). Histologically, no difference was observed in brain amyloid plaque burden in 6E10 stained brain sections from the Abeta1-30E18E19-vaccinated mice, compared to vehicle treated mice. Furthermore, amyloid burden did not correlate with cognitive performance. Analysis of plaque burden in the K6Abeta1-30E18E19-immunized mice is underway, as well as measurements of brain levels of Abeta to determine if these values will provide a better correlation with cognitive performance. A robust antibody response and a diminished plaque burden may not be necessary for a therapeutic effect of Abeta derived vaccines
— id: 97630, year: 2003, vol: 2003, page: Abstract No. 133.10, stat: Journal Article,

Differential degradation of amyloid beta genetic variants associated with hereditary dementia or stroke by insulin-degrading enzyme
Morelli, Laura; Llovera, Ramiro; Gonzalez, Silvia A; Affranchino, Jose L; Prelli, Frances; Frangione, Blas; Ghiso, Jorge; Castano, Eduardo M
2003 Jun 27;278(26):23221-23226, Journal of biological chemistry
Inherited amino acid substitutions at position 21, 22, or 23 of amyloid beta (Abeta) lead to presenile dementia or stroke. Insulin-degrading enzyme (IDE) can hydrolyze Abeta wild type, yet whether IDE is capable of degrading Abeta bearing pathogenic substitutions is not known. We studied the degradation of all of the published Abeta genetic variants by recombinant rat IDE (rIDE). Monomeric Abeta wild type, Flemish (A21G), Italian (E22K), and Iowa (D23N) variants were readily degraded by rIDE with a similar efficiency. However, proteolysis of Abeta Dutch (E22Q) and Arctic (E22G) was significantly lower as compared with Abeta wild type and the rest of the mutant peptides. In the case of Abeta Dutch, inefficient proteolysis was related to a high content of beta structure as assessed by circular dichroism. All of the Abeta variants were cleaved at Glu3-Phe4 and Phe4-Arg5 in addition to the previously described major sites within positions 13-15 and 18-21. SDS-stable Abeta dimers were highly resistant to proteolysis by rIDE regardless of the variant, suggesting that IDE recognizes a conformation that is available for interaction only in monomeric Abeta. These results raise the possibility that upregulation of IDE may promote the clearance of soluble Abeta in hereditary forms of Abeta diseases
— id: 42004, year: 2003, vol: 278, page: 23221, stat: Journal Article,

Inherited amyloidoses and neurodegeneration : familial British dementia and familial Danish dementia
Revesz T; Ghiso J; Holton J; Frangione B
Neurodegeneration : the molecular pathology of dementia and movement disorders Basel Switzerland : International Society of Neuropathology, 2003,
— id: 5152, year: 2003, vol: , page: 380, stat: Chapter,

Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view
Revesz, Tamas; Ghiso, Jorge; Lashley, Tammaryn; Plant, Gordon; Rostagno, Agueda; Frangione, Blas; Holton, Janice L
2003 Sep;62(9):885-898, Journal of neuropathology & experimental neurology
Amyloid deposition can take place in the walls of arteries, arterioles, and, less often, capillaries and veins of the central nervous system, a phenomenon known as cerebral amyloid angiopathy (CAA). The major clinicopathological manifestations of CAA include cerebral hemorrhage, ischemic lesions, and dementia. CAA may be classified according to the amyloid protein deposited. In the most common form, sporadic CAA, and in CAA related to sporadic Alzheimer disease (AD). A beta deposition is characteristic. CAA can also be severe in variants of familial AD caused by mutations of the amyloid-beta precursor protein or presenilin-1 genes in which deposition of A beta variants and/or wild-type A beta occurs. Other amyloid proteins involved in familial CAAs include 1) the mutant cystatin C (ACys) in hereditary cerebral hemorrhage with amyloidosis of Icelandic type, 2) variant transthyretins (ATTR) in meningo-vascular amyloidoses, 3) mutated gelsolin (AGel) in familial amyloidosis of Finnish type, 4) disease-associated prion protein (PrP(Sc)) in a variant of the Gerstmann-Straussler-Scheinker syndrome, and 5) ABri and ADan in CAAs observed in the recently described BRI2 gene-related dementias, familial British dementia and familial Danish dementia, respectively. This review addresses issues related to the correlation between morphology, biochemistry, and genetics, and briefly discusses both the pathogenesis and animal models of CAAs
— id: 42002, year: 2003, vol: 62, page: 885, stat: Journal Article,

P - component in familial british and danish dementias
Rostagno, A. A.; McGinty, R.; Ng, D.; Lashley, T.; Holton, J.; Frangione, B.; Revesz, T.; Ghiso, J.
2003 ;2003(9):Abstract No. 203.3-Abstract No. 203.3, Society for Neuroscience Abstract Viewer & Itinerary Planner
P-component is a member of the pentraxin family of proteins that has been found associated with amyloid deposits in vivo in both systemic and localized forms of amyloidosis including AD. Recently, two novel familial forms of cerebrovascular amyloidosis have been described. These hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), both result from genetic alterations in the BRI2 gene and show striking clinical and neuropathological similarities with AD. Despite structural differences among the amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD) all these disorders are characterized by the presence of neurofibrillary tangles and parenchymal and vascular amyloid deposits co-localizing with reactive microglia and activation products of the complement cascade. Immunohistochemical studies of FBD and FDD brain tissue identified P-component associated with the amyloid lesions. Using affinity chromatography, ELISA binding assays and electrophoretic techniques we were able to demonstrate a specific binding interaction between P-component and ABri/ADan peptides, study the biochemical parameters of the interaction, and compare them with that of Abeta amyloid species. Our studies revealed a high affinity, Calcium dependent, saturable binding between P-component and ABri/ADan peptides with Kd values in the low nanomolar range and in the same order of magnitude to those resulting from the interaction of P-component with Abeta1-40 and Abeta1-42. The high affinity interaction of P-component with ABri and ADan peptides in vitro suggests a likely mechanism for their in vivo co-localization in FBD and FDD lesions. Whether the presence of P-component protects the ABri/ADan amyloid deposits from enzymatic degradation as demonstrated for other amyloids is being investigated
— id: 101616, year: 2003, vol: 2003, page: Abstract No. 203.3, stat: Journal Article,

Copper modulates prion infectivity
Sigurdsson, E. M.; Brown, D.; Alim, M. A.; Scholtzova, H.; Carp, R.; Meeker, H. C.; Prelli, F.; Frangione, B.; Wisniewski, T.
2003 ;2003(47):Abstract No. 631.2-46202, Society for Neuroscience Abstract Viewer & Itinerary Planner
The prion protein (PrP) is a copper binding protein; however, the role of copper in prion infection is unclear. Under some conditions copper facilitates refolding of denatured PrPSc into a protease resistant and infectious form. Hence copper may enhance the infectivity of the prion protein. To determine the feasibility of copper targeted therapy for prion disease, we treated mice (n=10 per group) with d-penicillamine (d-PEN; 100 mg/kg, i.p.), immediately following scrapie inoculation (139A strain, i.p.). Subsequent drug injections were daily, five days per week. d-PEN delayed the onset of prion disease in the mice (p=0.002). The effect was more pronounced at the 1000-fold dilution of agent (d-PEN=179 +- 3 days, VEH=165 +- 4, p=0.006), but a trend for a delay was observed at the 10-fold dilution (d-PEN=153 +- 2, VEH=146 +- 3, p=0.1). As expected, d-PEN reduced brain copper levels (p<0.01) by 26% (10-fold dil.; p=0.04) and 32% (1000-fold dil.; p=0.02), compared to control animals. Brain levels of iron and zinc were not reduced. To further support the notion that the therapeutic effect of d-PEN was mediated through its copper chelating properties, brain homogenates from terminally ill 139A infected mice were incubated with copper and d-PEN. Following a 72 h incubation, copper sulfate increased aggregation of the prion protein in a dose dependent manner, resulting in an enhanced resistance to proteinase K. This effect was counteracted by co-incubation with d-PEN. These findings support the proposed in vivo effect of d-PEN in delaying the onset of prion disease in these mice. Copper chelator-based therapy may benefit those incubating prion disease but this approach may be more effective at higher doses and/or in a multi-targeted combinational therapy
— id: 97631, year: 2003, vol: 2003, page: Abstract No. 631.2, stat: Journal Article,

Copper chelation delays the onset of prion disease
Sigurdsson, Einar M; Brown, David R; Alim, Muhammad A; Scholtzova, Henrieta; Carp, Richard; Meeker, Harry C; Prelli, Frances; Frangione, Blas; Wisniewski, Thomas
2003 Nov 21;278(47):46199-46202, Journal of biological chemistry
The prion protein (PrP) binds copper and under some conditions copper can facilitate its folding into a more protease resistant form. Hence, copper levels may influence the infectivity of the scrapie form of prion protein (PrPSc). To determine the feasibility of copper-targeted therapy for prion disease, we treated mice with a copper chelator, D-(-)-penicillamine (D-PEN), starting immediately following intraperitoneal scrapie inoculation. D-PEN delayed the onset of prion disease in the mice by about 11 days (p = 0.002), and reduced copper levels in brain by 29% (p < 0.01) and in blood by 22% (p = 0.03) compared with control animals. Levels of other metals were not significantly altered in the blood or brain. Modest correlation was observed between incubation period and levels of copper in brain (p = 0.08) or blood (p = 0.04), indicating that copper levels are only one of many factors that influence the rate of progression of prion disease. In vitro, copper dose-dependently enhanced the proteinase K resistance of the prion protein, and this effect was counteracted in a dose-dependent manner by co-incubation with D-PEN. Overall, these findings indicate that copper levels can influence the conformational state of PrP, thereby enhancing its infectivity, and this effect can be attenuated by chelator-based therapy
— id: 48185, year: 2003, vol: 278, page: 46199, stat: Journal Article,

Anti-prion antibodies for prophylaxis following prion exposure in mice
Sigurdsson, Einar M; Sy, Man-Sun; Li, Ruliang; Scholtzova, Henrieta; Kascsak, Richard J; Kascsak, Regina; Carp, Richard; Meeker, Harry C; Frangione, Blas; Wisniewski, Thomas
2003 Jan 23;336(3):185-187, Neuroscience letters
Prion disease is characterized by a conformational change of the normal form of the prion protein (PrP(C)) to the scrapie-associated form (PrP(Sc)). Since the emergence of new variant Creutzfeldt-Jakob disease a potentially large human population is at risk for developing prion disease. Currently, no effective treatment or form of post-exposure prophylaxis is available for prion disease. We recently showed that active immunization with recombinant PrP prolongs the incubation period of scrapie. Here we show that anti-PrP antibodies following prion exposure are effective at increasing the incubation period of the infection. Stimulation of the immune system is an important therapeutic target for the prion diseases, as well as for other neurodegenerative illnesses characterized by abnormal protein conformation
— id: 34146, year: 2003, vol: 336, page: 185, stat: Journal Article,

Biochemical analysis of Abeta amyloid deposits in the Iowa variant of Alzheimer's disease
Tomidokoro, Y.; Rostagno, A.; Greenberg, S.; Frangione, B.; Rebeck, W.; Ghiso, J.
2003 ;2003(9):Abstract No. 772.2-Abstract No. 772.2, Society for Neuroscience Abstract Viewer & Itinerary Planner
Several mutations within the Abeta sequence of the APP gene are associated with autosomal dominant cerebral amyloid angiopathy. An Asp to Asn mutation at position 23 of Abeta due to a single nucleotide change at codon 694 of the APP gene causes early onset dementia with leukoencephalopathy and cortical calcification in the Iowa kindred. Severe cerebral amyloid angiopathy and cortical pre-amyloid deposits as well as widespread neurofibrillary tangles are the main neuropathological features of the disease. We have extracted the deposited Abeta species from affected brain areas and biochemically analyzed them using a combination of immunoprecipitation, mass spectrometry, amino acid sequence and western blot analysis. Corroborating previous histological data, western blots with C-terminal specific antibodies revealed an extensive accumulation of Abetax-40 in cortical lesions whereas Abetax-42 was only a minor component. Amino acid sequence of the formic-acid soluble extracts showed high degree of N-terminal heterogeneity, being Abeta starting at position 2 (Ala) the predominant species followed by Abeta4 (Phe) and Abeta1 (Asp) in a 4:2:1 ratio, respectively. IP/mass spect confirmed the presence of Abeta1-40, Abeta2-40 and Abeta4-40 as well as minor components starting at Asp1 and Ala2 but ending at Gly38. Interestingly, amino acid sequence analysis demonstrated the presence of both Asp and Asn at position 23 of the Abeta sequence at a 1:4 ratio, respectively, indicating that the deposited amyloid is a mixture of mutant and wild-type Abeta. Whether one of them is an innocent bystander being recruited by the other (conformational mimicry) or both mutated and non-mutated Abeta peptides are important for the amyloidogenesis process in the Iowa family is being currently investigated
— id: 101617, year: 2003, vol: 2003, page: Abstract No. 772.2, stat: Journal Article,

Brain clearance of Alzheimer's amyloid-beta40 in the squirrel monkey: a SPECT study in a primate model of cerebral amyloid angiopathy
Bading, James R; Yamada, Shinya; Mackic, Jasmina B; Kirkman, Linda; Miller, Carol; Calero, Miguel; Ghiso, Jorge; Frangione, Blas; Zlokovic, Berislav V
2002 Jun;10(4):359-368, Journal of drug targeting
Squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Previous studies suggested that circulating amyloid-beta40 peptide (Abeta40) crosses the blood-brain barrier (BBB) and may therefore enhance cerebrovascular amyloidosis in aged squirrel monkeys. In the present study, we used single photon emission computed tomography (SPECT) to determine elimination of 123I-Abeta40 and 99mTc-DTPA, an extracellular marker, from the brain in squirrel monkeys at different age. Following intracerebral microinfusions, the time-activity brain clearance curves indicated bi-exponential removal of 123I-Abeta40 with an initial rapid washout (1.1 < or = t 1/2 < or = 2.7 h). This, plus the observed appearance of 123I-radioactivity in plasma suggest significant brain-to-blood transport. In contrast, 99mTc-DTPA was removed slowly by brain interstitial fluid bulk flow (monoexponential decay with 6.8 < or = t 1/2 < or = 16.8 h). A comparison of three middle aged (11-16 years old) vs. two old (22 yrs old) monkeys was consistent with an age-related decline in the BBB capacity to remove 123I-Abeta from the brain. This correlated with an age-dependent increase in A1beta40/42 cerebrovascular immunoreactivity and amyloid deposition. Thus, vascular clearance plays an important role in reducing Abeta levels in the squirrel monkey brain and impaired Abeta40 elimination across the BBB may contribute to the development of CAA
— id: 42008, year: 2002, vol: 10, page: 359, stat: Journal Article,

CATABOLISM OF HUMAN ABETA IN WILD - TYPE MICE
Calero, M.; Shayo, M.; Fleire, S.; Rostagno, A.; Frangione, B.; Ghiso, J.
2002 ;2002(9):Abstract No. 19.10-Abstract No. 19.10, Society for Neuroscience Abstract Viewer & Itinerary Planner
ABETA is the main component of amyloid deposits in Alzheimers disease. A soluble form (sABETA) identical to the deposited ABETA is found in biological fluids and has the ability to cross the blood-brain barrier. The primary structure of ABETA and sABETA are indistinguishable and it is not clear whether sABETA reflects systemic production, brain clearance, or both. The pharmacokinetic parameters of synthetic soluble ABETA40 and ABETA42 species labeled with 125I or 125I-tyramine cellobiose were studied. Blood was drawn at different time points after a single dose of intravenous bolus-injection of the ABETA peptides to assess the distribution and elimination phases. Tissues were harvested at the end the experiment to determine organ uptake. The liver was found to be the major organ responsible for the clearance (>60%). Liver perfusion with collagenase followed by cell fractionation demonstrated that hepatocytes uptake >87% of the peptides while only 2% was found associated with Kupffer cells. (125I)-tyramine cellobiose ABETAwas also present in the gallbladder and small intestine, pointing to the biliary excretion as one of the clearance mechanisms. TCA-precipitable counts in plasma decreased exponentially shortly after the i.v. injection, suggesting that hydrolysis/enzymatic degradation are also important. Less than 15% biotransformation occurs via conjugation to plasma proteins under the conditions tested. The findings indicate that the liver plays a major role in the catabolism of sABETA, an issue to be considered in view of the current attempts to use synthetic homologues for therapeutic use
— id: 101618, year: 2002, vol: 2002, page: Abstract No. 19.10, stat: Journal Article,

Catabolism of human amyloid beta in wild-type B6SJFL1/J mice
Calero, M; Shayo, M; Fleire, S; Frangione, B; Ghiso, J
2002 Jul-Aug;23(1):925-, Neurobiology of aging
— id: 32423, year: 2002, vol: 23, page: 925, stat: Journal Article,

Transport of the precursor protein of familiar British and Danish dementias into secretory vesicles in neuronal cells
Choi, S; Ghiso, J; Frangione, B; Levy, E
2002 Jul-Aug;23(1):66-, Neurobiology of aging
— id: 32407, year: 2002, vol: 23, page: 66, stat: Journal Article,

A safer vaccine for Alzheimer's disease?
Frangione, B; Wisniewski, T; Sigurdsson, EM
2002 Jul-Aug;23(1):1579-, Neurobiology of aging
— id: 32430, year: 2002, vol: 23, page: 1579, stat: Journal Article,

Involvement of apolipoprotein J (apo J) in brain amyloidosis
Ghiso, J; Calero, M; Magnotti, L; Ng, D; Rostagno, A; Frangione, B
2002 Jul-Aug;23(1):1475-, Neurobiology of aging
— id: 32427, year: 2002, vol: 23, page: 1475, stat: Journal Article,

Amyloidosis and Alzheimer's disease
Ghiso, Jorge; Frangione, Blas
2002 Dec 7;54(12):1539-1551, Advanced drug delivery reviews
Alzheimer's disease (AD) is the most frequent type of amyloidosis in humans and the commonest form of dementia. Extracellular Abeta amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy as well as intraneuronal neurofibrillary tangles co-exist in the brain parenchyma of AD patients, the cognitive areas being the most severely affected. This review focuses on the potential role of amyloid in the development of neurodegeneration and presents studies of AD and other unrelated inherited dementia syndromes associated with neuronal loss and amyloid deposition in the brain
— id: 39364, year: 2002, vol: 54, page: 1539, stat: Journal Article,

Tau in familial Danish dementia brain is similar, but not identical, to that found in familial British dementia and PHF- tau in Alzheimer's disease
Hanger, D; Gibb, G; Anderton, B; Ghiso, J; Rostagno, A; Frangione, B; Holton, J; Revesz, T
2002 Jul-Aug;23(1):1845-, Neurobiology of aging
— id: 32437, year: 2002, vol: 23, page: 1845, stat: Journal Article,

Familial British Dementia (FBD): a cerebral amyloidosis with systemic amyloid deposition
Holton J; Ghiso J; Lashley T; Ganguly M; Strand K; Rostagno A; Plant G; Frangione B; Revesz T
2002 ;28(2):148-148, Neuropathology & applied neurobiology
— id: 73971, year: 2002, vol: 28, page: 148, stat: Journal Article,

Morphological evidence of the activation of the classical complement pathway in the BRI gene-related dementias
Holton, J; Lashley, T; Revesz, T; Rostagno, A; Frangione, B; Ghiso, J
2002 Jul-Aug;23(1):774-, Neurobiology of aging
— id: 32416, year: 2002, vol: 23, page: 774, stat: Journal Article,

Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta
Holton, Janice L; Lashley, Tammaryn; Ghiso, Jorge; Braendgaard, Hans; Vidal, Ruben; Guerin, Christopher J; Gibb, Graham; Hanger, Diane P; Rostagno, Agueda; Anderton, Brian H; Strand, Catherine; Ayling, Hilary; Plant, Gordon; Frangione, Blas; Bojsen-Moller, Marie; Revesz, Tamas
2002 Mar;61(3):254-267, Journal of neuropathology & experimental neurology
Familial Danish dementia (FDD) is pathologically characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal protein deposits, and neurofibrillary degeneration. FDD is associated with a mutation of the BRI2 gene located on chromosome 13. In FDD there is a decamer duplication, which abolishes the normal stop codon, resulting in an extended precursor protein and the release of an amyloidogenic fragment, ADan. The aim of this study was to describe the major neuropathological changes in FDD and to assess the distribution of ADan lesions, neurofibrillary pathology, glial, and microglial response using conventional techniques, immunohistochemistry, confocal microscopy, and immunoelectron microscopy. We showed that ADan is widely distributed in the central nervous system (CNS) in the leptomeninges, blood vessels, and parenchyma. A predominance of parenchymal pre-amyloid (non-fibrillary) lesions was found. Abeta was also present in a proportion of both vascular and parenchymal lesions. There was severe neurofibrillary pathology, and tau immunoblotting revealed a triplet electrophoretic migration pattern comparable with PHF-tau. FDD is a novel form of CNS amyloidosis with extensive neurofibrillary degeneration occurring with parenchymal, predominantly pre-amyloid rather than amyloid, deposition. These findings support the notion that parenchymal amyloid fibril formation is not a prerequisite for the development of neurofibrillary tangles. The significance of concurrent ADan and Abeta deposition in FDD is under further investigation
— id: 42011, year: 2002, vol: 61, page: 254, stat: Journal Article,

Circulating amyloid-beta peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer's disease lesions
Mackic, Jasmina B; Bading, James; Ghiso, Jorge; Walker, Larry; Wisniewski, Thomas; Frangione, Blas; Zlokovic, Berislav V
2002 Jun;38(6):303-313, Vascular pharmacology
1. We studied cerebrovascular sequestration and blood-brain barrier (BBB) permeability to [125I]- or [123I]-labeled amyloid-beta peptides (A beta) in aged rhesus and aged squirrel monkey, the nonhuman primate models of cerebral beta-amyloidosis and cerebrovascular amyloid angiopathy (CAA), respectively. 2. In aged rhesus, the half-time of elimination of [125I]A beta 1-40, t1/2e, was faster by 1.34 h, the systemic clearance, Clss, increased by 4.21 ml/min/kg and the mean residence time of intact peptide in the circulation shortened by 2 h. 3. Cerebrovascular sequestration of [125I]A beta 1-40 was significant in aged squirrel monkey (20.8 ml/g x 10(2)), but undetectable in the rhesus. 4. The permeability surface area product, PS, for [14C]inulin was low in both species (0.11-0.18 ml/g/s x 10(6)) indicating an intact barrier. 5. The BBB permeability to A beta 1-40 was 34.8- and 13.7-fold higher than for [14C]inulin in aged squirrel and rhesus, respectively, suggesting a specialized A beta transport across the BBB. 6. The single photon computed emission tomography studies confirmed a saturable [123I]A beta 1-40 transport at the BBB in primates (Km = 40 nM). 7. Brain autoradiographic analysis of [125I]A beta 1-42 or [125I]A beta 1-40 after intracarotid infusions of radiotracers confirmed co-localization of the signal with A beta-immunoreactive plaques in rhesus monkeys. 8. Metabolism of [125I]A beta 1-40 in brain and plasma was slower in aged squirrel compared to aged rhesus, by 2.9- and 2.6-fold, respectively. 9. Thus, transport of circulating A beta across the BBB contributes to brain parenchymal accumulation of amyloid in aged nonhuman primates. Negligible capillary binding, rapid systemic and brain degradation, and accelerated body elimination of blood-borne A beta, may prevent the development of CAA in rhesus in contrast to squirrel monkeys
— id: 42006, year: 2002, vol: 38, page: 303, stat: Journal Article,

Vascular Amyloidosis in Neurodegenerative Conditions
Matsubara E; Shoji M; Abe K; Frangione B; Ghiso J
2002 Sep;15(7):439-444, Drug news & perspectives
Cerebral amyloid angiopathy defines the deposition of amyloid fibrils in the walls of medium- and small-size leptomeningeal and cortical arteries and arterioles. This condition is an important cause of cerebral hemorrhages and is also associated with cerebral infarctions and diffused white matter changes. In many instances, vascular amyloid deposits co-exist with intraneuronal neurofibrillary tangles, being the cognitive areas the most severely affected. However, the importance of cerebral amyloid angiopathy as a causative element in the process of neurodegeneration is still debatable. This review discusses inherited dementia syndromes associated with neuronal loss and amyloid deposition in the brain, with particular focus on familial Alzheimer's disease and chromosome 13 dementia. (c) 2002 Prous Science. All rights reserved
— id: 42005, year: 2002, vol: 15, page: 439, stat: Journal Article,

Platelet microparticles as carriers of soluble Alzheimer's amyloid beta (sAbeta)
Matsubara, E; Shoji, M; Murakami, T; Abe, K; Frangione, B; Ghiso, J
2002 Nov;977(6):340-348, Annals of the New York Academy of Sciences
— id: 42007, year: 2002, vol: 977, page: 340, stat: Journal Article,

Substitution at codon 22 reduces clearance of Alzheimer's amyloid-beta peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into blood
Monro, O R; Mackic, J B; Yamada, S; Segal, M B; Ghiso, J; Maurer, C; Calero, M; Frangione, B; Zlokovic, B V
2002 May-Jun;23(3):405-412, Neurobiology of aging
A point mutation of G to C at codon 693 of the amyloid-beta (Abeta) precursor protein gene results in Glu to Gln substitution at position 22 of the Abeta (AbetaQ22) associated with hereditary cerebrovascular amyloidosis with hemorrhage Dutch type. Factors that regulate AbetaQ22 levels in the central nervous system (CNS) are largely unknown. By using ventriculo-cisternal perfusion technique in guinea pigs, we demonstrated that clearance from the cerebrospinal fluid and transport from the CNS to blood of [(125)I]-AbetaQ22 (1 nM) were reduced by 36% and 52%, respectively, in comparison to the wild type Abeta(1-40) peptide. In contrast to significant uptake and transport of Abeta(1-40) across the brain capillaries and leptomeningeal vessels, AbetaQ22 was not taken up at these CNS vascular transport sites, which was associated with its 53% greater accumulation in the brain. The CNS clearance of Abeta(1-40) was half-saturated at 23.6 nM; AbetaQ22 had about 6.8-fold less affinity for the CNS efflux transporters and its elimination relied mainly on transport across the choroid plexus. Thus, the Dutch mutation impairs elimination of Abeta from brain by reducing its rapid transport across the blood-brain barrier and the vascular drainage pathways, which in turn may result in accumulation of the peptide around the blood vessels and in brain
— id: 42010, year: 2002, vol: 23, page: 405, stat: Journal Article,

The British and Danish forms of familial BRI dementia
Plant, GT; Braendgaard, H; Revesz, T; Vidal, R; Ghiso, J; Frangione, B
2002 Aug;73(2):223-223, Journal of neurology neurosurgery & psychiatry
— id: 32382, year: 2002, vol: 73, page: 223, stat: Journal Article,

Familial British dementia (FBD), a form of cerebral amyloidosis with systemic amyloid deposition
Revesz, T; Lashley, T; Ganguly, M; Strand, C; Plant, G; Holton, J; Ghiso, J; Rostagno, A; Frangione, B
2002 Jul-Aug;23(1):1759-, Neurobiology of aging
— id: 32434, year: 2002, vol: 23, page: 1759, stat: Journal Article,

Sporadic and familial cerebral amyloid angiopathies
Revesz, Tamas; Holton, Janice L; Lashley, Tammaryn; Plant, Gordon; Rostagno, Agueda; Ghiso, Jorge; Frangione, Blas
2002 Jul;12(3):343-357, Brain pathology
Cerebral amyloid angiopathy (CAA) is the term used to describe deposition of amyloid in the walls of arteries, arterioles and, less often, capillaries and veins of the central nervous system. CAAs are an important cause of cerebral hemorrhage and may also result in ischemic lesions and dementia. A number of amyloid proteins are known to cause CAA. The most common sporadic CAA, caused by A beta deposition, is associated with aging and is a common feature of Alzheimer disease (AD). CAA occurs in several familial conditions, including hereditary cerebral hemorrhage with amyloidosis of Icelandic type caused by deposition of mutant cystatin C, hereditary cerebral hemorrhage with amyloidosis Dutch type and familial AD with deposition of either A beta variants or wild-type A beta, the transthyretin-related meningo-vascular amyloidoses, gelsolin as well as familial prion disease-related CAAs and the recently described BRI2 gene-related CAAs in familial British dementia and familial Danish dementia. This review focuses on the morphological, biochemical, and genetic aspects as well as the clinical significance of CAAs with special emphasis on the BRI2 gene-related cerebrovascular amyloidoses. We also discuss data relevant to the pathomechanism of the different forms of CAA with an emphasis on the most common A beta-related types
— id: 42009, year: 2002, vol: 12, page: 343, stat: Journal Article,

Complement activation in chromosome 13 dementias
Rostagno, A; Magnotti, L; Tomidokoro, Y; Frangione, B; Ghiso, J; Revesz, T; Lashley, T; Holton, J
2002 Jul-Aug;23(1):1661-, Neurobiology of aging
— id: 32431, year: 2002, vol: 23, page: 1661, stat: Journal Article,

Complement activation in chromosome 13 dementias. Similarities with Alzheimer's disease
Rostagno, Agueda; Revesz, Tamas; Lashley, Tammaryn; Tomidokoro, Yasushi; Magnotti, Laura; Braendgaard, Hans; Plant, Gordon; Bojsen-Moller, Marie; Holton, Janice; Frangione, Blas; Ghiso, Jorge
2002 Dec 20;277(51):49782-49790, Journal of biological chemistry
Chromosome 13 dementias, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with neurodegeneration and cerebrovascular amyloidosis, with striking neuropathological similarities to Alzheimer's disease (AD). Despite the structural differences among the amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD), these disorders are all characterized by the presence of neurofibrillary tangles and parenchymal and vascular amyloid deposits co-localizing with markers of glial activation, suggestive of local inflammation. Proteins of the complement system and their pro-inflammatory activation products are among the inflammation markers associated with AD lesions. Immunohistochemistry of FBD and FDD brain sections demonstrated the presence of complement activation components of the classical and alternative pathways as well as the neo-epitope of the membrane attack complex. Hemolytic experiments and enzyme-linked immunosorbent assays specific for the activation products iC3b, C4d, Bb, and C5b-9 indicated that ABri and ADan are able to fully activate the complement cascade at levels comparable to those generated by Abeta1-42. ABri and ADan specifically bound C1q with high affinity and formed stable complexes in physiological conditions. Activation proceeds approximately 70-75% through the classical pathway while only approximately 25-30% seems to occur through the alternative pathway. The data suggest that the chronic inflammatory response generated by the amyloid peptides in vivo might be a contributing factor for the pathogenesis of FBD and FDD and, in more general terms, to other neurodegenerative conditions
— id: 39388, year: 2002, vol: 277, page: 49782, stat: Journal Article,

SAFETY OF POTENTIAL VACCINES FOR ALZHEIMER'S DISEASE
Scholtzova, H.; Wisniewski, T.; Ahlawat, S.; Watanabe, M.; Quartermain, D.; Frangione, B.; Sigurdsson, E. M.
2002 ;2002(6):Abstract No. 227.1-46202, Society for Neuroscience Abstract Viewer & Itinerary Planner
Abeta1-42 vaccination trials were recently terminated because of cerebral inflammation, which may be due to Abeta toxicity and/or autoimmunity. Abeta forms inflammatory/toxic fibrils, may seed fibril formation and crosses the blood brain barrier (BBB) in experimental animals. Because of attenuated immune response, the elderly may not clear injected Abeta1-42, which may then initiate and/or enhance amyloid angiopathy and plaque formation. Therefore, it is safer to use immunogenic Abeta derivatives, which are less likely to be toxic. Unlike Abeta1-42, K6Abeta1-30 is non-fibrillogenic and non-toxic in human cell culture but diminishes amyloid burden to a similar extent as reported for Abeta1-42. Additionally, ramified IL-1beta positive microglia, associated with the plaques, are absent in the immunized mice indicating reduced inflammation in these animals. We are currently comparing the therapeutic potential of these two compounds in alum adjuvants, which are approved for human use. Our behavioral findings in a year old Tg2576 mice show no difference between these groups and controls in various sensorimotor tasks, linear maze and water maze. However, in the radial arm maze, vaccinated Tg mice and their non-Tg littermates performed equally well and had fewer errors than Tg controls (p=0.008). These groups are being evaluated at a higher amyloid burden and subsequently their brain pathology will be assessed. Overall, the use of nontoxic Abeta derivatives and/or Abeta clearing compounds with very limited access into the CNS, such as IgM, may prove to have reduced side effects compared to Abeta and/or IgG-based immunization
— id: 97632, year: 2002, vol: 2002, page: Abstract No. 227.1, stat: Journal Article,

VACCINATION DELAYS THE ONSET OF PRION DISEASE IN MICE
Sigurdsson, E. M.; Brown, D. R.; Daniels, M.; Kascsak, R. J.; Kascsak, R.; Carp, R.; Meeker, H. C.; Watanabe, M.; Scholtzova, H.; Frangione, B.; Wisniewski, T.
2002 ;2002(6):Abstract No. 692.15-413, Society for Neuroscience Abstract Viewer & Itinerary Planner
The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially large population being at risk to develop this prionosis. None of the prionoses currently have an effective treatment. Recently, vaccination has shown therapeutic potential in mouse models of another neurodegenerative condition, namely Alzheimers disease. Here we report that immunization with recombinant mouse prion protein delays the onset of prion disease in mice (Am. J. Pathol., in press). Vaccination was performed both prior to and after peripheral exposure to the mouse-adapted scrapie strain 139A. A delay in disease onset was seen in both groups, but was more prolonged in animals immunized prior to exposure (p = 0.040-0.002). The increase in the incubation period closely correlated with the anti-prion antibody titer (p = 0.017-0.0001). Histological and Western blot evaluations of the brains of the treated-and control groups did not reveal any apparent differences in the degree of spongiform change or levels of scrapie prion. This was expected because the mice were killed when they scored positive for three consecutive weeks for behavioral signs of prion infection. Overall, the vaccination-mediated delay in prion disease onset is highly reproducible, correlates well with antibody titer and indicates that a similar approach may work in humans or other mammalian species at risk for prion disease
— id: 97633, year: 2002, vol: 2002, page: Abstract No. 692.15, stat: Journal Article,

Immunization delays the onset of prion disease in mice
Sigurdsson, Einar M; Brown, David R; Daniels, Maki; Kascsak, Richard J; Kascsak, Regina; Carp, Richard; Meeker, Harry C; Frangione, Blas; Wisniewski, Thomas
2002 Jul;161(1):13-17, American journal of pathology
The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially large population being at risk to develop this prionosis. None of the prionoses currently have an effective treatment. Recently, vaccination has been shown to be effective in mouse models of another neurodegenerative condition, namely Alzheimer's disease. Here we report that vaccination with recombinant mouse prion protein delays the onset of prion disease in mice. Vaccination was performed both before peripheral prion exposure and after exposure. A delay in disease onset was seen in both groups, but was more prolonged in animals immunized before exposure. The increase in the incubation period closely correlated with the anti-prion protein antibody titer. This promising finding suggests that a similar approach may work in humans or other mammalian species at risk for prion disease
— id: 32479, year: 2002, vol: 161, page: 13, stat: Journal Article,

A safer vaccine for Alzheimer's disease?
Sigurdsson, Einar M; Wisniewski, Thomas; Frangione, Blas
2002 Nov-Dec;23(6):1001-1008, Neurobiology of aging
Recent reports indicate that amyloid-beta (Abeta) vaccine-based therapy for Alzheimer's disease (AD) may be on the horizon. There are, however, concerns about the safety of this approach. Immunization with Abeta1-42 may not be appropriate in humans because it crosses the blood-brain barrier, can seed fibril formation, and is highly fibrillogenic. Abeta1-42 fibrils can in turn cause inflammation and neurotoxicity. This issue is of a particular concern in the elderly who often do not mount an adequate immune response to vaccines. Our findings show that vaccination with nonamyloidogenic/nontoxic Abeta derivative may be a safer therapeutic approach to impede the progression of Abeta-related histopathology in AD. Although the site of action of the anti-Abeta antibodies has been suggested to be within the brain, peripheral clearance of Abeta may have a greater role in reducing cerebral amyloid plaques in these animals and eventually in AD patients. Antibodies in general are predominantly found outside the central nervous system (CNS) and will, therefore, primarily clear systemic Abeta compared to brain Abeta. This disruption of the equilibrium between central and peripheral Abeta should then result in efflux of Abeta out of the brain, and subsequent removal of plaques. Abeta therapy can be targeted to the periphery, which may result in fewer CNS side effects, such as inflammation. Future Abeta derived vaccines should include T(h) epitopes, carriers and/or lipid moieties to enhance antibody production in the elderly, the population predominantly affected by AD
— id: 32918, year: 2002, vol: 23, page: 1001, stat: Journal Article,

Infectivity of amyloid diseases
Sigurdsson, Einar M; Wisniewski, Thomas; Frangione, Blas
2002 Sep;8(9):411-413, Trends in molecular medicine
To date, transmissibility of amyloid diseases has not been thoroughly investigated. Although only some of these conformational disorders are considered infectious, all amyloid diseases could be infectious under certain conditions. For transmissibility, endogenous expression of an amyloidogenic peptide required, as well as the presence of an inoculum that is rich in amyloid fibrils and/or their precursors. Notably, administration of one type of amyloid might result in deposition of a different amyloid. Various cofactors could be essential for transmission - some might chaperone the amyloid peptides and/or fibrils, thereby directly facilitating their propagation; others might indirectly stabilize and/or increase levels of conformers with a high beta-sheet content. It is possible that these chaperones are induced by inflammation, which itself can lead to secondary amyloidosis. Thus, amyloid-related therapeutic approaches should not be based on administration of amyloidogenic peptides in conjunction with an inflammatory stimulus, such as in a recently halted clinical trial for Alzheimer's disease
— id: 32920, year: 2002, vol: 8, page: 411, stat: Journal Article,

Immunization for Alzheimer's disease
Sigurdsson, EM; Frangione, B; Wisniewski, T
2002 Jun;56(2):135-142, Drug development research
The recent termination of a Phase II clinical trial in which volunteers with Alzheimer's disease (AD) were vaccinated with Amyloid-beta (AP)1-42, has cast doubt on the feasibility of this therapeutic approach. While the exact reasons for the cerebral inflammation in these patients is being determined, it is difficult to evaluate the cause of these adverse effects. The most likely reasons are Abeta1-42 toxicity and/or autoimmunity. Abeta vaccination approaches are based on the hypothesis that Abeta deposition and toxicity are central to the pathogenesis of AD. Therefore, it is counterintuitive to use the whole Abeta peptide for human vaccination. Abeta1-40/42 is a major plaque component that forms inflammatory/toxic fibrils as observed in many in vitro and in vivo studies. Furthermore, numerous studies have shown that Abeta1-40/42 bidirectionally crosses the blood-brain barrier (BBB) in experimental animals. Additionally, in vitro and in vivo studies indicate that minute amounts of Abeta1-42 may seed fibril/amyloid formation. The elderly, a target population for AD therapy, often have a poor immune response to vaccines, which enhances the gravity of these safety concerns. In these patients with an attenuated immune reaction, injected Abeta1-42 may initiate and/or enhance congophilic angiopathy, which eventually may result in reduced cerebral blood flow and/or intracerebral bleeding. Abeta1-42 may also cross the BBB and once within the brain parenchyma it may contribute to plaque formation and/or co-deposit on plaques. Together, these effects within blood vessels and/or brain parenchyma may actually enhance the progression of AD. Given the potential serious side effects of Abeta1-42 vaccination, it is safer to use immunogenic Abeta derivatives, which are less likely to be toxic. The main immunogenic epitopes of Abeta1-42 are contained within the first 30 amino acids of the peptide. Taking this into account, we have developed soluble antigenic Abeta derivatives, which are nonfibrillogenic and nontoxic in human cell culture. Our prototype peptide, K6Abeta1-30-NHz, diminishes amyloid burden to a similar extent as reported for Abeta1-42. Additionally, ramified IL-1beta-positive microglia as well as phagocytes, associated with the Abeta plaques, were absent in the immunized mice, indicating reduced inflammation in these animals at the time point examined. Autoimmunity may be the culprit if follow-up studies reveal that the brain inflammation is related to antibody interactions with AD and/or amyloid precursor protein (APP). In such a scenario, any vaccination approach targeting A(3 can have similar consequences, although preventive treatment initiated prior to amyloid deposition may not result in these adverse reactions. T-cell-related autoimmunity may also be involved and can be expected to be less with Abeta derivatives not containing certain T-cell epitopes. An alternative to the active vaccination approach is passive immunization, which is associated with a lower risk of irreversible autoimmunity. This approach may also be used in patients with a muted immune response to the vaccine. However, in a chronic disease such as AD repeated antibody injections may lead to an anti-idiotype response and the resulting serum immune complexes can cause vasculitis and/or glomerulonephritis. Reduction of soluble Abeta within the peripheral system may be a critical part of the pathway that reduces cerebral plaque burden in Tg mice and ultimately in AD patients. Overall, the use of nontoxic A(3 derivatives and/or antibodies with very limited access into the CNS, such as IgM, may prove to have reduced si Any therapeutic approach will be more effective when used prophylactically because of neuronal loss and increased amyloid burden in the later stages of AD. Reversal of clinical symptoms cannot be expected and early diagnosis of AD may be needed for effective therapy. (C) 2002 Wiley-Liss, Inc
— id: 32447, year: 2002, vol: 56, page: 135, stat: Journal Article,

FAMILIAL DANISH DEMENT
Tomidokoro, Y.; Frangione, B.; Lashley, T.; Fleire, S.; Rostagno, A.; Holton, J.; Houlden, H.; Bojsen-Moller, M.; Braendgaard, H.; Plant, G.; Revesz, T.; Ghiso, J.
2002 ;2002(1):Abstract No. 328.9-Abstract No. 328.9, Society for Neuroscience Abstract Viewer & Itinerary Planner
Familial Danish Dementia (FDD) is an early onset autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia and dementia. Cerebral ADan amyloid and pre-amyloid deposits as well as NFTs in the hippocampus are the main neuropathological features of the disease. Surprisingly, Abeta was also found co-deposited in the amyloid lesions. We have biochemically characterized by immunoprecipitation, mass spectrometry, amino acid sequence and/or immunoblot analysis the ADan/Abeta species found in amyloid and pre-amyloid lesions in FDD brain and investigated the presence of soluble ADan and Abeta in plasma from carriers of the disease. ADan was composed by a mixture of full-length and C-terminal truncated species bearing N-terminal pyroglutamate (4044.6 Da). Abeta was mainly 1-42 and 4-42. Plasma soluble ADan contained N-terminal glutamate (4062.6 Da). The difference of 18 mass units accounts for the loss of one molecule of water. The conversion glutamate-pyroglutamate is chemically irreversible, indicating that sADan does not represent ADan being cleared from the brain amyloid but rather from soluble unmodified sADan species systemically produced and/or transported from the brain soluble pool. Thus, patients with FDD have two different types of amyloid molecules deposited in the brain and their respective soluble precursors are present in biological fluids. The significance of these unusual findings will be discussed
— id: 101619, year: 2002, vol: 2002, page: Abstract No. 328.9, stat: Journal Article,

Co-existence of amyloid ADan and amyloid-beta in familial Danish dementia
Tomidokoro, Y; Fleire, S; Rostagno, A; Frangione, B; Ghiso, J; Lashley, T; Holton, J; Houlden, H; Revesz, T; Bojsen-Moller, M; Braendgaard, H; Plant, G
2002 Jul-Aug;23(1):1663-, Neurobiology of aging
— id: 32432, year: 2002, vol: 23, page: 1663, stat: Journal Article,

Amyloid fibril protein nomenclature -- 2002
Westermark, Per; Benson, Merrill D; Buxbaum, Joel N; Cohen, Alan S; Frangione, Blas; Ikeda, Shu-ichi; Masters, Colin L; Merlini, Giampaolo; Saraiva, Maria J; Sipe, Jean D
2002 Sep;9(3):197-200, Amyloid
— id: 99111, year: 2002, vol: 9, page: 197, stat: Journal Article,

PASSIVE IMMUNIZATION WITH ANTI - PrP ANTIBODIES PROLONGS PRION INCUBATION PERIOD
Wisniewski, T.; Sy, M. S.; Li, R.; Scholtzova, H.; Kascsak, R. J.; Kascsak, R.; Carp, R.; Meeker, H. C.; Frangione, B.; Sigurdsson, E. M.
2002 ;2002(6):Abstract No. 692.16-413, Society for Neuroscience Abstract Viewer & Itinerary Planner
The prion diseases are a rapidly fatal group of neurodegenerative disorders, which currently have no effective therapy. Recently we have shown that active immunization with recombinant PrP protein increases the incubation period in mice exposed peripherally to the 139A strain of scrapie agent (Am.J.Pathol., in press). The antibody titers correlated with the increased incubation. We have extended these observations by using 6 different monoclonal anti-mouse PrP antibodies for passive immunization, with epitopes that span the murine PrP protein. Intraperitoneal antibody injections were performed weekly, starting immediately after and 1 month following peripheral exposure to scrapie strain 139A at two different dilutions. We found a statistically significant prolongation of the incubation period from scrapie exposure to the onset of clinical symptoms. These initial findings suggest that passive immunization can be used to prolong the incubation period among individuals with a known exposure to the prion agent
— id: 97634, year: 2002, vol: 2002, page: Abstract No. 692.16, stat: Journal Article,

Vaccination delays the onset of prion disease in mice
Wisniewski, T; Scholtzova, H; Watanabe, M; Ji, Y; Frangione, B; Sigurdsson, EM; Brown, DR; Daniels, M; Kasesak, RJ; Kascsak, R
2002 Jul-Aug;23(1):496-, Neurobiology of aging
— id: 32412, year: 2002, vol: 23, page: 496, stat: Journal Article,

Distinct properties of wild-type and the amyloidogenic human cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type
Calero M; Pawlik M; Soto C; Castano EM; Sigurdsson EM; Kumar A; Gallo G; Frangione B; Levy E
2001 Apr;77(2):628-637, Journal of neurochemistry
Variant human cystatin C (L68Q) is an amyloidogenic protein. It deposits in the cerebral vasculature of Icelandic patients with cerebral amyloid angiopathy, leading to stroke. Wild-type and variant cystatin C are cysteine proteinase inhibitors which form concentration dependent inactive dimers; however, variant cystatin C dimerizes at lower concentrations and has an increased susceptibility to a serine protease. We studied the effect of the L68Q amino acid substitution on cystatin C properties, utilizing full length cystatin C purified in mild conditions from media of cells stably transfected with either the wild-type or variant cystatin C genes. The variant cystatin C forms fibrils in vitro detectable by electron microscopy in conditions in which the wild-type protein forms amorphous aggregates. We also show by circular dichroism, steady-state fluorescence and Fourier-transformed infrared spectroscopy that the amino acid substitution modifies cystatin C structure by destabilizing alpha-helical structures and exposing the tryptophan residue to a more polar environment, yielding a more unfolded molecule. These spectral changes demonstrate that variant cystatin C has a three-dimensional structure different from that of the wild-type protein. The structural differences between variant and wild-type cystatin C account for the susceptibility of the variant protein to unfolding, proteolysis and fibrillogenesis
— id: 20351, year: 2001, vol: 77, page: 628, stat: Journal Article,

Familial cerebral amyloid angiopathy related to stroke and dementia
Frangione B; Revesz T; Vidal R; Holton J; Lashley T; Houlden H; Wood N; Rostagno A; Plant G; Ghiso J
2001 Jul;8 Suppl 1(1):36-42, Amyloid
The term cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the walls of leptomeningeal and cortical arteries, arterioles and, although less frequently in capillaries and veins. It is commonly associated with Alzheimers disease, Down's syndrome and normal aging, as well as with a variety of familial conditions related to stroke and/or dementia: hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-I), various inherited disorders linked to Abeta mutants (including the Dutch variant of HCHWA), and the recently described chromosome 13 familial dementia in British and Danish kindreds. This review focuses on four different types of hereditary CAA, emphasizing the notion that CAA is not only related to stroke but also to neurodegeneration and dementia of the Alzheimer's type
— id: 39471, year: 2001, vol: 8 Suppl 1, page: 36, stat: Journal Article,

Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia
Ghiso J; Frangione B
2001 Feb;3(1):65-73, Journal of Alzheimer's Disease
Cerebral amyloid angiopathy (CAA) is the common term used to define the deposition of amyloid in the walls of medium- and small-size leptomeningeal and cortical arteries, arterioles and, less frequently, capillaries and veins. CAA is an important cause of cerebral hemorrhages although it may also lead to ischemic infarction and dementia. It is a feature commonly associated with normal aging, Alzheimer disease (AD), Down syndrome (DS), and Sporadic Cerebral Amyloid Angiopathy. Familial conditions in which amyloid is chiefly deposited as CAA include hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-I), familial CAA related to Abeta variants, including hereditary cerebral hemorrhage with amyloidosis of Dutch origin (HCHWA-D), the transthyretin-related meningocerebrovascular amyloidosis of Hungarian and Ohio kindreds, the gelsolin-related spinal and cerebral amyloid angiopathy, familial PrP-CAA, and the recently described chromosome 13 familial dementia in British and Danish kindreds. This review focuses on the various molecules and genetic variants that target the cerebral vessel walls producing clinical features related to stroke and/or dementia, and discusses the potential role of amyloid in the mechanism of neurodegeneration
— id: 39451, year: 2001, vol: 3, page: 65, stat: Journal Article,

Chromosome 13 dementia syndromes as models of neurodegeneration
Ghiso J; Revesz T; Holton J; Rostagno A; Lashley T; Houlden H; Gibb G; Anderton B; Bek T; Bojsen-Moller M; Wood N; Vidal R; Braendgaard H; Plant G; Frangione B
2001 Dec;8(4):277-284, Amyloid
Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in Alzheimer's disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain
— id: 32472, year: 2001, vol: 8, page: 277, stat: Journal Article,

Famililal British dementia
Ghiso J; Revesz T; Rostagno A; Vidal R; Plant G; Frangione B
Alzheimer's disease : advances in etiology, pathogenesis and therapeutics New York : Wiley, 2001,
— id: 5111, year: 2001, vol: , page: 487, stat: Chapter,

Familial British dementia
Ghiso J; Revesz T; Rostango A; Vidal R; Plant G; Frangione B
Alzheimer's Disease : advances in etiology, pathogenesis and therapeutics Chichester : John Wiley, 2001,
— id: 3843, year: 2001, vol: , page: 487, stat: Chapter,

A newly formed amyloidogenic fragment due to a stop codon mutation causes familial British dementia
Ghiso J; Vidal R; Rostagno A; Mead S; Revesz T; Plant G; Frangione B
2001 ;3:12-13, Dementia reviews
— id: 73974, year: 2001, vol: 3, page: 12, stat: Journal Article,

Systemic Amyloid Deposits in Familial British Dementia
Ghiso JA; Holton J; Miravalle L; Calero M; Lashley T; Vidal R; Houlden H; Wood N; Neubert TA; Rostagno A; Plant G; Revesz T; Frangione B
2001 Nov 23;276(47):43909-43914, Journal of biological chemistry
Familial British dementia (FBD) is an early onset inherited disorder that, like familial Alzheimer's disease (FAD), is characterized by progressive dementia, amyloid deposition in the brain, and neurofibrillary degeneration of limbic neurons. The primary structure of the amyloid subunit (ABri) extracted from FBD brain tissues (Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G., and Ghiso, J. (1999) Nature 399, 776-781) is entirely different and unrelated to any previously known amyloid protein. Patients with FBD have a single nucleotide substitution at codon 267 in the BRI2 gene, resulting in an arginine replacing the stop codon and a longer open reading frame of 277 amino acids instead of 266. The ABri peptide comprises the 34 C-terminal residues of the mutated precursor ABriPP-277 and is generated via furin-like proteolytic processing. Here we report that carriers of the Stop-to-Arg mutation have a soluble form of the amyloid peptide (sABri) in the circulation with an estimated concentration in the range of 20 ng/ml, several fold higher than that of soluble Abeta. In addition, ABri species identical to those identified in the brain were also found as fibrillar components of amyloid deposits predominantly in the blood vessels of several peripheral tissues, including pancreas and myocardium. We hypothesize that the high concentration of the soluble de novo created amyloidogenic peptide and/or the insufficient tissue clearance are the main causative factors for the formation of amyloid deposits outside the brain. Thus, FBD constitutes the first documented cerebral amyloidosis associated with neurodegeneration and dementia in which the amyloid deposition is also systemic
— id: 23926, year: 2001, vol: 276, page: 43909, stat: Journal Article,

Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia
Holton JL; Ghiso J; Lashley T; Rostagno A; Guerin CJ; Gibb G; Houlden H; Ayling H; Martinian L; Anderton BH; Wood NW; Vidal R; Plant G; Frangione B; Revesz T
2001 Feb;158(2):515-526, American journal of pathology
Familial British dementia (FBD), pathologically characterized by cerebral amyloid angiopathy (CAA), amyloid plaques, and neurofibrillary degeneration, is associated with a stop codon mutation in the BRI gene resulting in the production of an amyloidogenic fragment, amyloid-Bri (ABri). The aim of this study was to assess the distribution of ABri fibrillar and nonfibrillar lesions and their relationship to neurofibrillary pathology, astroglial and microglial response using immunohistochemistry, confocal microscopy, and immunoelectron microscopy in five cases of FBD. Abnormal tau was studied with immunoblotting. We present evidence that ABri is deposited throughout the central nervous system in blood vessels and parenchyma where both amyloid (fibrillar) and pre-amyloid (nonfibrillar) lesions are formed. Ultrastructurally amyloid lesions appear as bundles of fibrils recognized by an antibody raised against ABri, whereas Thioflavin S-negative diffuse deposits consist of amorphous electron-dense material with sparse, dispersed fibrils. In contrast to nonfibrillar lesions, fibrillar ABri is associated with a marked astrocytic and microglial response. Neurofibrillary tangles and neuropil threads occurring mainly in limbic structures, are found in areas affected by all types of ABri lesions whereas abnormal neurites are present around amyloid lesions. Immunoblotting for tau revealed a triplet electrophoretic migration pattern. Our observations confirm a close link between ABri deposition and neurodegeneration in FBD
— id: 42013, year: 2001, vol: 158, page: 515, stat: Journal Article,

Familial Danish dementia (FDD); A novel form of cerebral amyloidosis associated with deposition of two amyloidogenic peptides
Holton, JL; Lashley, T; Vidal, R; Rostagno, A; Gibb, G; Anderton, BH; Braendgaard, H; Plant, GT; Bojsen-Moller, M; Ghiso, J; Frangione, B; Revesz, T
2001 MAY ;60(5):536-536, Journal of neuropathology & experimental neurology
— id: 55068, year: 2001, vol: 60, page: 536, stat: Journal Article,

Retinal angiopathy in the British and Danish forms of Familial BRI Dementia
Plant, GT; Guerin, CJ; Holton, J; Houlden, H; Braendgaard, H; Bek, T; Ghiso, J; Frangione, B; Revesz, T
2001 MAR 15 ;42(4):S648-S648, Investigative ophthalmology & visual science. IOVS
— id: 54980, year: 2001, vol: 42, page: S648, stat: Journal Article,

Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Abeta peptide
Poeggeler B; Miravalle L; Zagorski MG; Wisniewski T; Chyan YJ; Zhang Y; Shao H; Bryant-Thomas T; Vidal R; Frangione B; Ghiso J; Pappolla MA
2001 Dec 11;40(49):14995-15001, Biochemistry
Inheritance of apoE4 is a strong risk factor for the development of late-onset sporadic Alzheimer's disease (AD). Several lines of evidence suggest that apoE4 binds to the Alzheimer Abeta protein and, under certain experimental conditions, promotes formation of beta-sheet structures and amyloid fibrils. Deposition of amyloid fibrils is a critical step in the development of AD. We report here that addition of melatonin to Abeta in the presence of apoE resulted in a potent isoform-specific inhibition of fibril formation, the extent of which was far greater than that of the inhibition produced by melatonin alone. This effect was structure-dependent and unrelated to the antioxidant properties of melatonin, since it could be reproduced neither with the structurally related indole N-acetyl-5-hydroxytryptamine nor with the antioxidants ascorbate, alpha-tocophenol, and PBN. The enhanced inhibitory effects of melatonin and apoE were lost when bovine serum albumin was substituted for apoE. In addition, Abeta in combination with apoE was highly neurotoxic (apoE4 > apoE3) to neuronal cells in culture, and this activity was also prevented by melatonin. These findings suggest that reductions in brain melatonin, which occur during aging, may contribute to a proamyloidogenic microenvironment in the aging brain
— id: 42012, year: 2001, vol: 40, page: 14995, stat: Journal Article,

Deposition of amyloid-BRI (ABri) is associated with neurofibrillary degeneration in familial British dementia (FBD)
Revesz, T; Lashley, T; Vidal, R; Rostagno, K; Gibb, G; Anderton, BH; Plant, G; Frangione, B; Ghiso, J; Holton, JL
2001 MAY ;60(5):536-536, Journal of neuropathology & experimental neurology
— id: 55069, year: 2001, vol: 60, page: 536, stat: Journal Article,

Complement activation in Bri dementias and Alzheimer's disease
Rostagno, A.; Revesz, T.; Holton, J.; Lashley, T.; Frangione, B.; Ghiso, J.
2001 ;27(2):2562-2562, Abstracts (Society for Neuroscience)
Familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the CNS and neurodegeneration. Amyloids ABri and ADan are C-terminal degradation products of the same precursor BriPP codified by the chromosome 13 BRI2 gene bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide insertion before the stop codon in FDD. Both de novo created amyloid peptides are 34 amino acids long, share 100% identity of the first 22 residues and pyroglutamate at their N-terminus. Neuritic components and NFTs containing PHF co-localize with the amyloid deposits in both disorders and the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in AD. To explore the role of inflammatory factors in these familial disorders, complement activation was assessed via immunohistochemistry, hemolytic assays and ELISA. Components and activation products (i.e. C1q, iC3b, C3d, C4d, C5b-9) were found to co-localize with plaques and vascular deposits in both diseases, suggesting in situ activation. ABri and ADan synthetic peptides activated the classical pathway in vitro and resulted in the formation of the activation products iC3b, C4d and SC5b-9 at levels comparable to those generated by Abeta42. The ability of ABri and ADan to trigger the complement cascade in vitro together with the presence of complement proteins and activation products as integral components of parenchymal and vascular amyloid deposits suggest that, as indicated in AD, the complement system may contribute to the mechanism of neurodegeneration leading to dementia
— id: 101620, year: 2001, vol: 27, page: 2562, stat: Journal Article,

Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice
Sigurdsson EM; Scholtzova H; Mehta PD; Frangione B; Wisniewski T
2001 Aug;159(2):439-447, American journal of pathology
Transgenic mice with brain amyloid-beta (Abeta) plaques immunized with aggregated Abeta1-42 have reduced cerebral amyloid burden. However, the use of Abeta1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic Abeta homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% (P = 0.0002) and 81% (P = 0.0001), respectively. Concurrently, brain levels of soluble Abeta1-42 were reduced by 57% (P = 0.0019). Ramified microglia expressing interleukin-1beta associated with the Abeta plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic Abeta derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Abeta fibrils
— id: 23485, year: 2001, vol: 159, page: 439, stat: Journal Article,

Immunization with a soluble and non-toxic amyloid-beta derivative substantially impedes Alzheimer's disease associated pathology in transgenic mice
Sigurdsson, E. M.; Schwaninger, J.; Scholtzova, H.; Mehta, P. D.; Ji, Y.; Ahlawat, S.; Sparks, C. M.; Quartermain, D.; Frangione, B.; Wisniewski, T.
2001 ;27(2):1807-447, Abstracts (Society for Neuroscience)
Transgenic mice with brain amyloid-beta (Abeta) plaques immunized with aggregated Abeta1-42 have reduced cerebral amyloid burden. However, the use of Abeta1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and it can seed fibril formation. We report that immunization in 11-12 months old Tg2576 APP mice for 7 months, with K6Abeta1-30, a highly soluble, non-amyloidogenic and non-toxic Abeta homologous peptide, reduced cortical and hippocampal brain amyloid burden by 89% (p=0.0002) and 81% (p=0.0001), respectively. Concurrently, brain levels of soluble Abeta1-42 were reduced by 57% (p=0.0019). Ramified microglia expressing interleukin-1beta associated with the Abeta plaques were absent in the immunized mice, indicating reduced inflammation in these animals. We are currently performing a long-term study on the histological, biochemical and behavioral effects of K6Abeta1-30 vaccination, where the mice received their first immunization at 2-4 months of age. Our preliminary results are that mice immunized with K6Abeta1-30 or Abeta1-42 in aluminum adjuvants have comparable titers although the former is much more soluble. Overall, our present findings suggest that immunization with soluble Abeta derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Abeta aggregates
— id: 97635, year: 2001, vol: 27, page: 1807, stat: Journal Article,

A 7-kDa prion protein (PrP) fragment, an integral component of the PrP region required for infectivity, is the major amyloid protein in Gerstmann-Straussler-Scheinker disease A117V
Tagliavini F; Lievens PM; Tranchant C; Warter JM; Mohr M; Giaccone G; Perini F; Rossi G; Salmona M; Piccardo P; Ghetti B; Beavis RC; Bugiani O; Frangione B; Prelli F
2001 Feb 23;276(8):6009-6015, Journal of biological chemistry
Gerstmann-Straussler-Scheinker disease (GSS) is a cerebral amyloidosis associated with mutations in the prion protein (PrP) gene (PRNP). The aim of this study was to characterize amyloid peptides purified from brain tissue of a patient with the A117V mutation who was Met/Val heterozygous at codon 129, Val(129) being in coupling phase with mutant Val117. The major peptide extracted from amyloid fibrils was a approximately 7-kDa PrP fragment. Sequence analysis and mass spectrometry showed that this fragment had ragged N and C termini, starting mainly at Gly88 and Gly90 and ending with Arg148, Glu152, or Asn153. Only Val was present at positions 117 and 129, indicating that the amyloid protein originated from mutant PrP molecules. In addition to the approximately 7-kDa peptides, the amyloid fraction contained N- and C-terminal PrP fragments corresponding to residues 23-41, 191-205, and 217-228. Fibrillogenesis in vitro with synthetic peptides corresponding to PrP fragments extracted from brain tissue showed that peptide PrP-(85-148) readily assembled into amyloid fibrils. Peptide PrP-(191-205) also formed fibrillary structures although with different morphology, whereas peptides PrP-(23-41) and PrP-(217-228) did not. These findings suggest that the processing of mutant PrP isoforms associated with Gerstmann-Straussler-Scheinker disease may occur extracellularly. It is conceivable that full-length PrP and/or large PrP peptides are deposited in the extracellular compartment, partially degraded by proteases and further digested by tissue endopeptidases, originating a approximately 7-kDa protease-resistant core that is similar in patients with different mutations. Furthermore, the present data suggest that C-terminal fragments of PrP may participate in amyloid formation
— id: 35704, year: 2001, vol: 276, page: 6009, stat: Journal Article,

Sequence, genomic structure and tissue expression of Human BRI3, a member of the BRI gene family
Vidal R; Calero M; Revesz T; Plant G; Ghiso J; Frangione B
2001 Mar 21;266(1-2):95-102, Gene
The BRI3 gene is a member of the BRI gene family, made up of at least three different genes (BRI1-3). Previous studies established the cDNA sequence and structure of the human and mouse BRI1 and BRI2 genes and we recently reported that mutations in the BRI2 isoform, located on chromosome 13, are associated with dementia in humans. In the present work, we determine the complete cDNA sequence and genomic organization of the human BRI3 gene. BRI3 codes for a polypeptide of 267 amino acids, with a Mr of 30 KDa and a pI of 8.47. The amino acid sequence is 43.7% identical to the sequence of the human BRI2, and 38.3% identical to that of human BRI1, with the highest percentage of amino acid identity being concentrated on the C-terminal half of the molecules. In Northern blots, BRI3 cDNA hybridizes only one message of approximately 2.1 kilobases, which is predominantly present in the human brain. The BRI3 gene is localized on chromosome 2 and consists of six exons spanning more than 20 kb. Homology search of EST data banks retrieved a Caenorhabditis briggsae homolog of BRI, indicating that the BRI gene belongs to a strongly conserved gene family. These studies, aimed at characterizing the members of the BRI gene family, may provide valuable clues to the understanding of their normal function and how mutations in BRI2 can cause neurodegeneration and dementia similar to Alzheimer's disease
— id: 21212, year: 2001, vol: 266, page: 95, stat: Journal Article,

A dacamer duplication in the BRI gene originates a de novo amyloid peptide that causes dementia in a Danish kindred
Vidal R; Revesz T; Rostango A; Bek T; Braendgaard H; Plant G; Ghiso J; Frangione B
Alzheimer's Disease : advances in etiology, pathogenesis and therapeutics Chichester : John Wiley, 2001,
— id: 3844, year: 2001, vol: , page: 507, stat: Chapter,

Conformation as a therapeutic target in the prionoses and other neurodegenerative conditions
Wisniewski T; Sigurdsson EM; Aucouturier P; Frangione B
Molecular pathology of the prions Totowa NJ: Humana Press, 2001,
— id: 2638, year: 2001, vol: , page: ?, stat: Chapter,

Conformation as therapeutic target in the prionoses and other neurodegenerative conditions
Wisniewski, T; Sigurdsson, E M; Aucouturier, P; Frangione, B
2001 ;59:223-236, Methods in molecular medicine
Neurodegenerative conditions are increasing in prevalence as the average human life expectancy rises. Alzheimer's disease (AD) is the fourth commonest cause of death in the United States; the recent outbreak of new variant Creutzfeldt-Jakob disease (nvCJD) has raised the specter of a large population being at risk to develop this prionosis. The pathogenesis of many neurodegenerative diseases is now recognized to be associated with abnormalities of protein conformation. A common theme in these disorders is the conversion of a soluble normal precursor protein into an insoluble, aggregated, ?-sheet rich form that is toxic. In AD, a critical event is the conversion of the normal, soluble A? (sA?) peptide into fibrillar A?, within neuritic plaques and congophilic angiopathy (1). Similarly, in the prionoses, the central event is the conversion of the normal prion protein, PrPC, to PrPSc (2). An increased ?-sheet content characterizes both A? and PrPSc
— id: 126513, year: 2001, vol: 59, page: 223, stat: Journal Article,

Inclusion body myositis, muscle blood vessel and cardiac amyloidosis, and transthyretin Val122Ile allele
Askanas V; Engel WK; Alvarez RB; Frangione B; Ghiso J; Vidal R
2000 Apr;47(4):544-549, Annals of neurology
Typical of sporadic inclusion body myositis muscle biopsies are vacuolated muscle fibers containing intracellular amyloid deposits and accumulations of 'Alzheimer-characteristic' proteins. There is no muscle blood vessel or cardiac amyloidosis. We report on a 70-year-old African-American man homozygous for the transthyretin Val122Ile allele who has both sporadic inclusion body myositis and cardiac amyloidosis. His unique pathological features included transthyretin immunoreactivity in prominent muscle blood vessel amyloid and congophilic amyloid deposits within vacuolated muscle fibers
— id: 9381, year: 2000, vol: 47, page: 544, stat: Journal Article,

Fasciola hepatica: parasite-secreted proteinases degrade all human IgG subclasses: determination of the specific cleavage sites and identification of the immunoglobulin fragments produced
Berasain P; Carmona C; Frangione B; Dalton JP; Goni F
2000 Feb;94(2):99-110, Experimental parasitology
The study was focused on the relation ship of Fasciola hepatica-secreted proteinases and human IgG subclasses. Each IgG was incubated at different pH values and lengths of time with either the adult parasite excretion-secretion products or the purified cysteinyl proteinases cathepsin L1 and cathepsin L2. The Ig fragments produced were isolated and characterized by Western blot analysis, and the specific cleavage sites were determined by amino acid sequence analysis. Parasite excretion-secretion products and both cathepsins L produced similar degradation patterns and cleaved all human IgG subclasses at the hinge region, yielding at pH 7.3 and 37 degrees C Fab and Fc fragments in the case of IgG1 and IgG3 or Fab(2) and Fc in IgG2 and IgG4. While IgG1 and IgG3 were readily degraded by E/S products either in the presence or in the absence of reducing agents, IgG2 and IgG4 were resistant to proteolysis and were only digested in the presence of 0.1 M dithiothreitol. The cathepsins L needed the presence of dithiothreitol to digest IgG1, IgG2, and IgG4 whereas IgG3 was identically cleaved under both reducing and nonreducing conditions. The main cleavage sites produced by E/S products, CL1, or CL2 were located at the positions peptide bonds: His237-Thr238, Glu237-Cys239, Gly233-Asp234, and Ser241-Cys242 for gamma1, gamma2, gamma3, or gamma4, respectively. The enzymes gave additional splitting sites on the middle hinge of IgG3 to produce shorter Fc fragments and also produce Fd degradation of the IgG4. No cleavage specificity differences were found between CL1 and CL2, but they differed in the kinetics of IgG3 degradation. By lowering the pH, only the E/S products produced concomitant destruction of the Fc while preserving the Fab portion. Under all the conditions assayed the enzymes produced an Fc'-like fragment of 14-15 kDa corresponding to the whole CH3 domain of the immunoglobulin. Contrary to the extensive degradation produced by cathepsins on digested proteins, its actions on IgG subclasses were specific and restricted; thus, all the fragments produced could be potentially involved in the mechanisms used by the parasite to evade the host immune response.
— id: 9500, year: 2000, vol: 94, page: 99, stat: Journal Article,

Apolipoprotein J (clusterin) and Alzheimer's disease [In Process Citation]
Calero M; Rostagno A; Matsubara E; Zlokovic B; Frangione B; Ghiso J
2000 Aug 15;50(4):305-315, Microscopy research & technique
Apolipoprotein J (clusterin) is a ubiquitous multifunctional glycoprotein capable of interacting with a broad spectrum of molecules. In pathological conditions, it is an amyloid associated protein, co-localizing with fibrillar deposits in systemic and localized amyloid disorders. In Alzheimer's disease, the most frequent form of amyloidosis in humans and the major cause of dementia in the elderly, apoJ is present in amyloid plaques and cerebrovascular deposits but is rarely seen in NFT-containing neurons. ApoJ expression is up-regulated in a wide variety of insults and may represent a defense response against local damage to neurons. Four different mechanisms of action could be postulated to explain the role of apoJ as a neuroprotectant during cellular stress: (1) function as an anti-apoptotic signal, (2) protection against oxidative stress, (3) inhibition of the membrane attack complex of complement proteins locally activated as a result of inflammation, and (4) binding to hydrophobic regions of partially unfolded, stressed proteins, and therefore avoiding aggregation in a chaperone-like manner. This review focuses on the association of apoJ in biological fluids with Alzheimer's soluble Abeta. This interaction prevents Abeta aggregation and fibrillization and modulates its blood-brain barrier transport at the cerebrovascular endothelium.
— id: 9372, year: 2000, vol: 50, page: 305, stat: Journal Article,

Familial cerebral amyloid angiopathies and dementia [In Process Citation]
Frangione B; Vidal R; Rostagno A; Ghiso J
2000 ;14 Suppl 1:S25-S30, Alzheimer disease & associated disorders
Amyloidosis is a disorder of protein conformation leading to aggregation. The term defines a diverse group of proteins normally present in body fluids as soluble precursors that can be deposited as insoluble amyloid fibrils in different tissues producing organ dysfunction and cell death. These fibrils are composed of self-assembled, low molecular weight mass peptides adopting beta-pleated sheet structure, the conformation responsible for their physicochemical properties and tinctoreal characteristics. So far, 20 different proteins have been identified as subunits of amyloid fibrils (Westermark et al., 1999). Collectively, they are products of normal genes; however, several amyloid precursors contain abnormal amino acid substitutions that can impose an unusual potential for self-aggregation. The molecular mass of the amyloid peptides is within the 4 to 30-kDa range, with heterogeneity at the amino- and carboxyl-terminal portions found in most amyloid proteins. Increased levels of amyloid precursors, either in the circulation or locally in sites of deposition, are usually the result of overexpression or defective clearance, or both. Of the 20 amyloid proteins identified, few of them are known to cause amyloid deposition in the central nervous system, which in turn results in cognitive deficits, dementia, stroke, cerebellar and extrapyramidal signs, or a combination of them
— id: 9374, year: 2000, vol: 14 Suppl 1, page: S25, stat: Journal Article,

Neuropathology and genetics of Prion protein and British cerebral amyloid angiopathies
Ghetti B; Piccardo P; Frangione B; Vidal R; Ghiso J
Cerebral amyloid angiopathy in Alzheimer's disease and related disorders Boston : Kluwer, 2000,
— id: 5150, year: 2000, vol: , page: 237, stat: Chapter,

A newly formed amyloidogenic fragment due to a stop codon mutation causes familial British dementia
Ghiso J; Vidal R; Rostagno A; Mead S; Revesz T; Plant G; Frangione B
2000 Apr;903:129-137, Annals of the New York Academy of Sciences
Familial British dementia (FBD) is an early-onset autosomal dominant disorder characterized by progressive cognitive impairment, spasticity, and cerebellar ataxia. Hippocampal neurofibrillar degeneration and widespread parenchymal and vascular amyloid deposits are the main neuropathological lesions. Amyloid fibrils are composed of a novel 34 amino acid subunit (ABri) with no sequence identity to any known amyloid molecule. The peptide derives from a larger precursor protein codified by a single gene BRI on chromosome 13. Affected family members have a single base substitution at the stop codon of the BRI gene that generates a longer open-reading frame resulting in a larger precursor protein. The release of the 34 C-terminal amino acids from the mutated precursor originates the ABri amyloid subunit. Our discovery of a new amyloid associated with the development of dementia supports the concept that amyloid peptides may be of primary importance in the initiation of neurodegeneration
— id: 9377, year: 2000, vol: 903, page: 129, stat: Journal Article,

Amyloidogenesis in familial British dementia is associated with a genetic defect on chromosome 13
Ghiso J; Vidal R; Rostagno A; Miravalle L; Holton JL; Mead S; Revesz T; Plant G; Frangione B
2000 ;920(1):84-92, Annals of the New York Academy of Sciences
Familial British dementia (FBD) is a disorder characterized by the presence of amyloid deposits in cerebral blood vessels and brain parenchyma coexisting with neurofibrillary tangles in limbic areas. The amyloid subunit (ABri) is a 4 kDa fragment of a 266 amino acid type II single-spanning transmembrane precursor protein encoded by the BRI gene located on chromosome 13. In FBD patients, a single base substitution at the stop codon of this gene generates a larger 277-residue precursor (ABriPP-277). Proteolytic processing by a furin-like enzyme at the C-terminus of the elongated precursor generates the 34 amino acid ABri that undergoes rapid aggregation and fibrillization. ABri is structually unrelated to all known amyloids including A beta, the main component of the amyloid lesions in Alzheimer's disease (AD), indicating that cerebral deposition of amyloid molecules other than A beta can trigger similar neuropathological changes leading to neuronal loss and dementia. These data support the concept that amyloid deposition in the vascular wall and brain parenchyma is of primary importance in the initiation of neurogeneration
— id: 39490, year: 2000, vol: 920, page: 84, stat: Journal Article,

Familial British dementia is a systemic amyloidosis
Ghiso, J.; Miravalle, L.; Calero, M.; Vidal, R.; Holden, H.; Holton, J.; Lashley, T.; Rostagno, A.; Wood, N.; Revesz, T.; Plant, G.; Frangione, B.
2000 ;26(1-2):Abstract No.-201.11, Abstracts (Society for Neuroscience)
Familial British dementia (FBD) is an autosomal dominant neurodegenerative disorder clinically characterized by progressive dementia, spastic tetraparesis and cerebellar ataxia, with an age of onset in the fourth decade. The neuropathology of FBD (amyloid angiopathy, parenchymal plaques and neurofibrillary tangles) is similar to that of AD. Amyloid deposits in cerebral blood vessels and parenchymal plaques are mainly composed of a 4 kDa subunit, ^ABri, derived from a type II transmembrane precursor molecule mutated at the stop codon. The mutation produces a longer open reading frame that generates a larger 277 aa precursor. ^ABri is a 34 amino acids peptide released by proteolytic processing of the C-terminus of the mutated precursor protein (ABriPP277). We have identified soluble ABri (sABri) in serum and CSF of patients with FBD using a combination of immunoprecipitation, mass spectrometry and western blot analysis. The 4 kDa component was present in all tested carriers of the Stop-to-Arg mutation and consistently absent in non-carrier family members and normal controls. In contrast to the CNS-deposited ^ABri, sABri was monomeric and devoided of N-terminal pyroglutamate. In view of these findings, we tested systemic organs in an autopsy case of FBD for amyloid deposits. Antibodies specific to the ^ABri peptide labeled Congo red positive vascular lesions in several peripheral organs; in addition, parenchymal immunoreactivity was also seen in many of the tissues tested. Biochemical analysis of the deposited material isolated from pancreas, uterus and skeletal muscle identified ^ABri species similar to those found in amyloid lesions in the CNS (Nature, 399:776,1999). The main component was full-length ABri featuring N-terminus pyroglutamate. The data indicate that amyloid formation in FBD occurs not only in the brain but also peripherally. This is the first case of cerebral amyloidosis associated with neurodegeneration in demented patients where the amyloid deposition is also systemic
— id: 101621, year: 2000, vol: 26, page: Abstract No., stat: Journal Article,

Familial British dementia: Immunohistochemical and immunoelectron microscopic study
Holton, JL; Lashley, T; Vidal, R; Rostagno, A; Guerin, CJ; Houlden, H; Plant, G; Frangione, B; Ghiso, J; Revesz, T
2000 SEP ;10(4):713-714, Brain pathology
— id: 73961, year: 2000, vol: 10, page: 713, stat: Journal Article,

Familial British dementia with amyloid angiopathy: early clinical, neuropsychological and imaging findings
Mead S; James-Galton M; Revesz T; Doshi RB; Harwood G; Pan EL; Ghiso J; Frangione B; Plant G
2000 May;123(Pt 5):975-991, Brain
Familial British dementia with amyloid angiopathy (FBD) is an autosomal dominant condition characterized by a dementia, progressive spastic tetraparesis and cerebellar ataxia with onset in the sixth decade. A point mutation in the BRI gene has been shown to be the genetic abnormality. Genealogical work with the large family originally reported by Worster-Drought and updated by Plant has identified nine generations dating back to the late eighteenth century. The pedigree now includes six living affected patients, 35 historical cases, and 52 descendants at risk of having inherited the disease. A common ancestor has been identified between the large pedigree and a case report of 'familial cerebellar ataxia with amyloid angiopathy'. An autopsy case from a separate family with an identical condition is described but no common ancestor with the large pedigree has been found. Case histories have been researched and updated in each pedigree. Eleven individuals at risk of FBD, aged between 44 and 56 years, agreed to undergo a clinical and neuropsychological assessment along with MRI brain imaging in order to clarify early diagnostic features. Five of the eleven were thought to show early clinical signs of the disease. Neurological examination was abnormal in three, with limb and gait ataxia and mild spastic paraparesis. Three had impaired recognition and recall memory and another had mild impairment of delayed visual recall. All affected individuals had an abnormal MRI of the brain, consisting of deep white-matter hyperintensity (T(2)-weighted scans) and lacunar infarcts, but no intracerebral haemorrhage. The corpus callosum was affected particularly, and in one patient it was severely atrophic
— id: 9380, year: 2000, vol: 123, page: 975, stat: Journal Article,

Substitutions at codon 22 of Alzheimer's abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells [In Process Citation]
Miravalle L; Tokuda T; Chiarle R; Giaccone G; Bugiani O; Tagliavini F; Frangione B; Ghiso J
2000 Sep 1;275(35):27110-27116, Journal of biological chemistry
Cerebral amyloid angiopathy is commonly associated with normal aging and Alzheimer's disease and it is also the principal feature of hereditary cerebral hemorrhage with amyloidosis Dutch type, a familial condition associated to a point mutation G to C at codon 693 of the amyloid beta (Abeta) precursor protein gene resulting in a Glu to Gln substitution at position 22 of the Abeta (E22Q). The patients carrying the AbetaE22Q variant usually present with lobar cerebral hemorrhages before 50 years of age. A different mutation described in several members of three Italian kindred who presented with recurrent hemorrhagic strokes late in life, between 60 and 70 years of age, also associated with extensive cerebrovascular amyloid deposition has been found at the same position 22, this time resulting in a Glu to Lys substitution (E22K). We have compared the secondary structure, aggregation, and fibrillization properties of the two Abeta40 variants and the wild type peptide. Using flow cytometry analysis after staining with propidium iodide and annexin V, we also evaluated the cytotoxic effects of the peptides on human cerebral endothelial cells in culture. Under the conditions tested, the E22Q peptide exhibited the highest content of beta-sheet conformation and the fastest aggregation/fibrillization properties. The Dutch variant also induced apoptosis of cerebral endothelial cells at a concentration of 25 &mgr;m, whereas the wild type Abeta and the E22K mutant had no effect. The data suggest that different amino acids at position 22 confer distinct structural properties to the peptides that appear to influence the onset and aggressiveness of the disease rather than the phenotype
— id: 9376, year: 2000, vol: 275, page: 27110, stat: Journal Article,

An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer's disease [In Process Citation]
Pappolla MA; Chyan YJ; Poeggeler B; Frangione B; Wilson G; Ghiso J; Reiter RJ
2000 ;107(2):203-231, Journal of neural transmission
This review summarizes recent advancements in our understanding of the potential role of the amyloid beta protein in Alzheimer's disease. It also discusses the significance of amyloid beta in initiating the generation of partially reduced oxygen species and points out their role in damaging essential macromolecules in the CNS which leads to neuronal dysfunction and loss. Recently acquired experimental data links these destructive oxidative processes with some neurodegenerative aspects of Alzheimer's disease. The experimental findings related to the free radical scavenging and antioxidative properties of melatonin are tabulated and its efficacy and the likely mechanisms involved in its ability to reduce neuronal damage mediated by oxygen-based reactive species in experimental models of Alzheimer's disease are summarized. Besides the direct scavenging properties and indirect antioxidant actions of melatonin, its ability to protect neurons probably also stems from its antiamyloidogenic properties. Melatonin is also unique because of the ease with which it passes through the blood-brain barrier
— id: 9375, year: 2000, vol: 107, page: 203, stat: Journal Article,

Dementia associated with amyloid beta angiopathy, tau perivascular pathology and APOE epsilon 4 genotype
Piccardo, P; Vidal, R; Calero, M; Farlow, MR; Unverzagt, FW; Gomez-Tortosa, E; Ghiso, J; Hyman, B; Frangione, B; Ghetti, B
2000 SEP ;10(4):714-714, Brain pathology
— id: 54519, year: 2000, vol: 10, page: 714, stat: Journal Article,

Cerebral deposition of ABRI amyloid in Familial British Dementia
Revesz T; Holton J; Vidal R; Rostagno A; Lashley T; Plant G; Frangione B; Ghiso J
2000 ;21:S191-S191, Neurobiology of aging
— id: 73972, year: 2000, vol: 21, page: S191, stat: Journal Article,

Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier
Shibata M; Yamada S; Kumar SR; Calero M; Bading J; Frangione B; Holtzman DM; Miller CA; Strickland DK; Ghiso J; Zlokovic BV
2000 Dec;106(12):1489-1499, Journal of clinical investigation
Elimination of amyloid-ss peptide (Ass) from the brain is poorly understood. After intracerebral microinjections in young mice, (125)I-Ass(1-40) was rapidly removed from the brain (t(1/2) </= 25 minutes), mainly by vascular transport across the blood-brain barrier (BBB). The efflux transport system for Ass(1-40) at the BBB was half saturated at 15.3 nM, and the maximal transport capacity was reached between 70 nM and 100 nM. Ass(1-40) clearance was substantially inhibited by the receptor-associated protein, and by antibodies against LDL receptor-related protein-1 (LRP-1) and alpha(2)-macroglobulin (alpha(2)M). As compared to adult wild-type mice, clearance was significantly reduced in young and old apolipoprotein E (apoE) knockout mice, and in old wild-type mice. There was no evidence that Ass was metabolized in brain interstitial fluid and degraded to smaller peptide fragments and amino acids before its transport across the BBB into the circulation. LRP-1, although abundant in brain microvessels in young mice, was downregulated in older animals, and this downregulation correlated with regional Ass accumulation in brains of Alzheimer's disease (AD) patients. We conclude that the BBB removes Ass from the brain largely via age-dependent, LRP-1-mediated transport that is influenced by alpha(2)M and/or apoE, and may be impaired in AD
— id: 42015, year: 2000, vol: 106, page: 1489, stat: Journal Article,

In vivo reversal of amyloid-beta lesions in rat brain
Sigurdsson EM; Permanne B; Soto C; Wisniewski T; Frangione B
2000 Jan;59(1):11-17, Journal of neuropathology & experimental neurology
Cerebral amyloid-beta (Abeta) deposition is central to the neuropathological definition of Alzheimer disease (AD) with Abeta related toxicity being linked to its beta-sheet conformation and/or aggregation. We show that a beta-sheet breaker peptide (iAbeta5) dose-dependently and reproducibly induced in vivo disassembly of fibrillar amyloid deposits, with control peptides having no effect. The iAbeta5-induced disassembly prevented and/or reversed neuronal shrinkage caused by Abeta and reduced the extent of interleukin-1beta positive microglia-like cells that surround the Abeta deposits. These findings suggest that beta-sheet breakers, such as iAbeta5 or similar peptidomimetic compounds, may be useful for reducing the size and/or number of cerebral amyloid plaques in AD, and subsequently diminishing Abeta-related histopathology
— id: 8565, year: 2000, vol: 59, page: 11, stat: Journal Article,

Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides
Soto C; Kascsak RJ; Saborio GP; Aucouturier P; Wisniewski T; Prelli F; Kascsak R; Mendez E; Harris DA; Ironside J; Tagliavini F; Carp RI; Frangione B
2000 Jan 15;355(9199):192-197, Lancet
BACKGROUND: Transmissible spongiform encephalopathies are associated with a structural transition in the prion protein that results in the conversion of the physiological PrPc to pathological PrP(Sc). We investigated whether this conformational transition can be inhibited and reversed by peptides homologous to the PrP fragments implicated in the abnormal folding, which contain specific residues acting as beta-sheet blockers (beta-sheet breaker peptides). METHODS: We studied the effect of a 13-residue beta-sheet breaker peptide (iPrP13) on the reversion of the abnormal structure and properties of PrP(Sc) purified from the brains of mice with experimental scrapie and from human beings affected by sporadic and variant Creutzfeldt-Jakob disease. In a cellular model of familial prion disease, we studied the effect of the peptide in the production of the abnormal form of PrP in intact cells. The influence of the peptide on prion infectivity was studied in vivo by incubation time assays in mice with experimental scrapie. FINDINGS: The beta-sheet breaker peptide partly reversed in-vitro PrP(Sc) to a biochemical and structural state similar to that of PrPc. The effect of the peptide was also detected in intact cells. Treatment of prion infectious material with iPrP13 delayed the appearance of clinical symptoms and decreased infectivity by 90-95% in mice with experimental scrapie. INTERPRETATION: Beta-sheet breaker peptides reverse PrP conformational changes implicated in the pathogenesis of spongiform encephalopathies. These peptides or their derivatives provide a useful tool to study the role of PrP conformation and might represent a novel therapeutic approach for prion-related disorders
— id: 8575, year: 2000, vol: 355, page: 192, stat: Journal Article,

In vitro evidence that beta-amyloid peptide 1-40 diffuses across the blood-brain barrier and affects its permeability
Strazielle N; Ghersi-Egea JF; Ghiso J; Dehouck MP; Frangione B; Patlak C; Fenstermacher J; Gorevic P
2000 Jan;59(1):29-38, Journal of neuropathology & experimental neurology
Beta amyloid peptides are major insoluble constituents of amyloid fibrils in senile plaques and cerebrovascular deposits, both characteristic of Alzheimer disease (AD). Low concentrations of soluble forms of amyloid peptides are also present in normal CSF. We previously demonstrated that the 40 amino acid form of soluble beta-amyloid peptide (sAbeta) is rapidly cleared from rat CSF into blood. Herein we hypothesized that a saturable, outwardly directed flux of this peptide occurs at the blood-brain barrier (BBB) and tested whether supraphysiological (possibly pathological) concentrations of sAbeta could alter the permeability of this barrier to a paracellular tracer, polyethylene glycol (PEG). Using an in vitro model of BBB, we showed that influx and efflux of sAbeta were equal, modest (60%-160% greater than that of PEG), and not saturable. These observations suggest that sAbeta moved across the monolayer by a diffusional process, and not via a transporter. PEG flux was doubled immediately after the luminal concentration of cold sAbeta was raised to 5 microM, and was doubled 150 min after the abluminal concentration of sAbeta was increased to 5 microM. Pathological elevations of sAbeta concentration in plasma or brain interstitial fluid may, therefore, alter the permeability of brain capillaries in vivo
— id: 57562, year: 2000, vol: 59, page: 29, stat: Journal Article,

Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid beta peptides
Tokuda T; Calero M; Matsubara E; Vidal R; Kumar A; Permanne B; Zlokovic B; Smith JD; Ladu MJ; Rostagno A; Frangione B; Ghiso J
2000 Jun 1;348 Pt 2:359-365, Biochemical journal
The inheritance of the apolipoprotein E (apoE) epsilon4 allele is a prevailing risk factor for sporadic and familial Alzheimer's disease (AD). ApoE isoforms bind directly to Alzheimer's amyloid beta (Abeta) peptides both in vitro and in vivo. Recent studies suggest that association of apoE with lipids may modulate its interaction with Abeta. We examined the binding of lipid-associated and delipidated apoE3 and apoE4 isoforms to Abeta utilizing a solid-phase binding assay and estimated the dissociation constants for the interaction of various apoE and Abeta species. Using native apoE isoforms from stably transfected RAW 264 and human embryonic kidney 293 cells, apoE3 had greater affinity than apoE4 for both Abeta1-40 and Abeta1-42. Delipidation of apoE decreased its affinity for Abeta peptides by 5-10-fold and abolished the isoform-specificity. Conversely, incorporation of apoE isoforms produced by baculovirus-infected Sf9 cells into reconstituted human high-density-lipoprotein lipoparticles restored the affinity values for Abeta peptides and resulted in preferential binding of apoE3. The data demonstrate that native lipid-associated apoE3 binds to Abeta peptides with 2-3-fold higher affinity than lipid-associated apoE4. Since the isoforms' binding efficiency correlate inversely with the risk of developing late-onset AD, the results suggest a possible involvement of apoE3 in the clearance or routing out of Abeta from the central nervous system as one of the mechanisms underlying the pathology of the disease
— id: 9378, year: 2000, vol: 348 Pt 2, page: 359, stat: Journal Article,

Senile dementia associated with amyloid beta protein angiopathy and tau perivascular pathology but not neuritic plaques in patients homozygous for the APOE-epsilon4 allele [In Process Citation]
Vidal R; Calero M; Piccardo P; Farlow MR; Unverzagt FW; Mendez E; Jimenez-Huete A; Beavis R; Gallo G; Gomez-Tortosa E; Ghiso J; Hyman BT; Frangione B; Ghetti B
2000 Jul;100(1):1-12, Acta neuropathologica
Amyloid beta protein deposition in cortical and leptomeningeal vessels, causing the most common type of cerebral amyloid angiopathy, is found in sporadic and familial Alzheimer's disease (AD) and is the principal feature in the hereditary cerebral hemorrhage with amyloidosis, Dutch type. The presence of the Apolipopriotein E (APOE)-epsilon4 allele has been implicated as a risk factor for AD and the development of cerebral amyloid angiopathy in AD. We report clinical, pathological and biochemical studies on two APOE-epsilon4 homozygous subjects, who had senile dementia and whose main neuropathological feature was a severe and diffuse amyloid angiopathy associated with perivascular tau neurofibrillary pathology. Amyloid beta protein and ApoE immunoreactivity were observed in leptomeningeal vessels as well as in medium-sized and small vessels and capillaries in the parenchyma of the neocortex, hippocampus, thalamus, cerebellum, midbrain, pons, and medulla. The predominant peptide form of amyloid beta protein was that terminating at residue Val40, as determined by immunohistochemistry, amino acid sequence and mass spectrometry analysis. A crown of tau-immunopositive cell processes was consistently present around blood vessels. DNA sequence analysis of the Amyloid Precursor Protein gene and Presenilin-1 (PS-1) gene revealed no mutations. In these APOE-epsilon4 homozygous patients, the pathological process differed from that typically seen in AD in that they showed a heavy burden of perivascular tau-immunopositive cell processes associated with severe amyloid beta protein angiopathy, neurofibrillary tangles, some cortical Lewy bodies and an absence of neuritic plaques. These cases emphasize the concept that tau deposits may be pathogenetically related to amyloid beta protein deposition
— id: 9373, year: 2000, vol: 100, page: 1, stat: Journal Article,

New familial forms of cerebral amyloid and dementia
Vidal R; Ghiso J; Frangione B
2000 Nov;5(6):575-576, Molecular psychiatry
— id: 42014, year: 2000, vol: 5, page: 575, stat: Journal Article,

A decamer duplication in the BRI gene originates a de novo amyloid peptide that causes dementia in a Danish kindred
Vidal R; Revesz T; Rostagno A; Bek T; Braengaard H; Plant G; Ghiso J; Frangione B
2000 ;21:S58-S58, Neurobiology of aging
— id: 101630, year: 2000, vol: 21, page: S58, stat: Journal Article,

A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred
Vidal R; Revesz T; Rostagno A; Kim E; Holton JL; Bek T; Bojsen-Moller M; Braendgaard H; Plant G; Ghiso J; Frangione B
2000 Apr 25;97(9):4920-4925, Proceedings of the National Academy of Sciences of the United States of America
Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri, the peptide originated by a point mutation at the stop codon of gene BRI in familial British dementia. Molecular genetic analysis of the BRI gene in the Danish kindred showed a different defect, namely the presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids. This de novo-created amyloidogenic peptide, associated with a genetic defect in the Danish kindred, stresses the importance of amyloid formation as a causative factor in neurodegeneration and dementia
— id: 9379, year: 2000, vol: 97, page: 4920, stat: Journal Article,

"Prion biology and diseases" by Stanley B. Prusiner
Wisniewski T; Frangione B
2000 ;342:983-983, New England journal of medicine
— id: 97679, year: 2000, vol: 342, page: 983, stat: Journal Article,

Vascular transport of Alzheimer's amyloid ? peptides and apolipoproteins
Zlokovic B; Ghiso J; Frangione B
Cerebral amyloid angiopathy in Alzheimer's disease and related disorders Boston : Kluwer, 2000,
— id: 5151, year: 2000, vol: , page: 325, stat: Chapter,

Clearance of amyloid beta-peptide from brain: transport or metabolism?
Zlokovic, B V; Yamada, S; Holtzman, D; Ghiso, J; Frangione, B
2000 Jul;6(7):718-719, Nature medicine
— id: 101674, year: 2000, vol: 6, page: 718, stat: Journal Article,

Prion diseases and the immune system
Aucouturier P; Frangione B; Wisniewski T
1999 Feb;150(2):75-78, Annales de medecine interne
Unlike other infectious diseases, transmissible spongiform encephalopathies elicit no specific immune response. Indeed, because the infectious agent, the prion, seems to be essentially composed of a protein with a primary structure identical to a host encoded protein, the lymphoid system is naturally tolerant. However, lymphoid organs are strongly implicated in the early peripheral steps of the disease. Paradoxically, immunodeficient animals, which are more susceptible to infections by usual pathogens, appear to be partially or completely resistant to experimental infection by prions by peripheral route. Several studies suggest that in normal subjects, cells of the immune system support the replication of prions and might allow their spreading from the periphery to the central nervous system. Thus, the lymphoid system appears to behave as a Trojan horse rather than a protective fortification in the process of prion infection. A greater understanding of the pathophysiology of these aspects of prion diseases could lead to immunomanipulation strategies aimed at preventing prion spread into the central nervous system, once peripheral exposure has occurred
— id: 8496, year: 1999, vol: 150, page: 75, stat: Journal Article,

Biochemical and conformational variability of human prion strains in sporadic Creutzfeldt-Jakob disease
Aucouturier P; Kascsak RJ; Frangione B; Wisniewski T
1999 Oct 15;274(1):33-36, Neuroscience letters
The pathogenesis of prion (PrP) diseases is thought to be related to conformational changes of a normal cellular protein, PrPC, into a protease resistant protein called PrPSc, which is infectious by itself. A difficulty with this 'protein only' hypothesis is the existence of numerous PrP strains, that require PrPSc to have multiple conformations. Sporadic Creutzfeldt-Jakob disease (CJD), which accounts for nearly 80% of human prionoses, was reported to include at least two 'strains' termed types 1 and 2 which differ by electrophoretic patterns of their proteinase K (PK)-resistant fragments (PrP27-30). We have analyzed the biochemical and structural properties of PrPSc and PrP27-30 isolates from six sporadic CJD patients. Fourier transform-infra-red spectroscopy, PrP27-30 glycosylation patterns and studies of PK sensitivity revealed a striking heterogeneity. Furthermore, one isolate yielded a PrP27-30 fragment with a lower mobility clearly different from previously described sporadic CJD types. Although the average beta-sheet content was higher among type 1 isolates, there was overlap between the two types. Our study suggests that human sporadic CJD-related prions display a significant heterogeneity
— id: 9501, year: 1999, vol: 274, page: 33, stat: Journal Article,

Biochemical and conformational variability of human prion strains in sporadic Creutzfeldt-Jakob disease
Aucouturier, Pierre; Kascsak, Richard J.; Quartermain, David; Frangione, Blas; Wisniewski, Thomas
1999 ;25(1-2):1854-78, Abstracts (Society for Neuroscience)
— id: 97636, year: 1999, vol: 25, page: 1854, stat: Journal Article,

Functional and structural properties of lipid-associated apolipoprotein J (clusterin)
Calero M; Tokuda T; Rostagno A; Kumar A; Zlokovic B; Frangione B; Ghiso J
1999 Dec 1;344 Pt 2:375-383, Biochemical journal
Apolipoprotein J (apoJ, clusterin) is a multifunctional protein normally associated with lipids in plasma and cerebrospinal fluid, and secreted as lipoparticles by hepatocytes and astrocytes. To investigate whether the structural and functional properties of apoJ are modulated upon binding to lipids, we prepared apoJ high-density lipoprotein (HDL)-like particles employing either synthetic or plasma HDL-derived lipids. The majority of the resulting lipoparticles contained one molecule of apoJ per particle and exhibited the same alpha2 electrophoretic mobility characteristic of apoJ-containing plasma HDL. Particle size seemed to be dependent on the presence of cholesterol in the lipid mixture and ranged from diameters of 10 nm in the presence of cholesterol to 20 nm in the absence of cholesterol. CD analysis and Fourier-transform infrared spectroscopy revealed similar changes in the apoJ secondary structure induced by its incorporation into lipoparticles, namely a decrease in alpha-helix content and an increase in beta-turn structures. Two functional assays, the binding interaction with Alzheimer's amyloid beta peptides and the inhibitory activity of the complement membrane-attack complex, did not detect any changes in apoJ activity following its lipidation (P>0.05). On the contrary, the binding affinity to the cellular receptor megalin was enhanced significantly (P<0.01) after the association with lipids; the K(d) value decreased from 78.8+/-10.7 nM for the delipidated form to 37. 0+/-7.3 nM for apoJ-HDL. Although it is not known whether the structural changes observed are directly responsible for the higher receptor-binding affinity, the data suggest that the complement inhibition and amyloid beta-binding motifs are located in areas of the molecule different from those involved in the apoJ-megalin interaction
— id: 9384, year: 1999, vol: 344 Pt 2, page: 375, stat: Journal Article,

Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid
Chyan YJ; Poeggeler B; Omar RA; Chain DG; Frangione B; Ghiso J; Pappolla MA
1999 Jul 30;274(31):21937-21942, Journal of biological chemistry
Widespread cerebral deposition of a 40-43-amino acid peptide called the amyloid beta-protein (Abeta) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer's disease. Numerous studies suggest that Abeta is toxic to neurons by free radical-mediated mechanisms. We have previously reported that melatonin prevents oxidative stress and death of neurons exposed to Abeta. In the process of screening indole compounds for neuroprotection against Abeta, potent neuroprotective properties were uncovered for an endogenous related species, indole-3-propionic acid (IPA). This compound has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. IPA completely protected primary neurons and neuroblastoma cells against oxidative damage and death caused by exposure to Abeta, by inhibition of superoxide dismutase, or by treatment with hydrogen peroxide. In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity. These findings may have therapeutic applications in a broad range of clinical situations
— id: 9387, year: 1999, vol: 274, page: 21937, stat: Journal Article,

Kappa light chain-associated Fanconi's syndrome: molecular analysis of monoclonal immunoglobulin light chains from patients with and without intracellular crystals
Deret S; Denoroy L; Lamarine M; Vidal R; Mougenot B; Frangione B; Stevens FJ; Ronco PM; Aucouturier P
1999 Apr;12(4):363-369, Protein engineering
Plasma cell dyscrasias may be responsible for Fanconi's syndrome, due to the toxicity of a free monoclonal kappa light chain toward kidney proximal tubules. Eight cases of Fanconi's syndrome were analyzed. We compared the structures of VkappaI variability subgroup V domains from five cases of Fanconi's syndrome and one myeloma without renal involvement. Among Fanconi cases, four putative structures were obtained after molecular modeling by homology, and the other had previously been refined by X-ray crystallography. The complete sequences of one VkappaI, one VkappaIII and N-terminal sequences of two VkappaI light chains, from patients with different forms of Fanconi's syndrome, were compared with four previously studied sequences. All three kappa chains responsible for a 'classical' form with intralysosomal crystals and a low mass myeloma, were encoded by the LCO2/O12 germline gene and had an unusual non-polar residue exposed to the solvent in the CDR-L1 loop. Of both VkappaI light chains from patients with Fanconi's syndrome without intracellular crystals, one derived from LCO2/O12 and the other from LCO8/O18 gene. Another feature that could be related to non-crystallization was the absence of accessible side chains in the CDR-L3 loop which is known to be implicated in dimer formation
— id: 9503, year: 1999, vol: 12, page: 363, stat: Journal Article,

Familial cerebrovascular amyloidosis with neurofibillary tangles causing dementia in British patients is due to a stop codon mutation of a novel gene BRI mapped to chromosome 13
Ghiso, J; Vidal, R; Rostagno, A; Mead, S; Revesz, T; Plant, G; Frangione, B
1999 Oct 23-28;25(1-2):297-297, Abstracts (Society for Neuroscience)
— id: 15871, year: 1999, vol: 25, page: 297, stat: Journal Article,

Lipoprotein-free amyloidogenic peptides in plasma are elevated in patients with sporadic Alzheimer's disease and Down's syndrome
Matsubara E; Ghiso J; Frangione B; Amari M; Tomidokoro Y; Ikeda Y; Harigaya Y; Okamoto K; Shoji M
1999 Apr;45(4):537-541, Annals of neurology
About 90% of the soluble amyloid beta (sA beta) that circulates in normal human plasma is associated with lipoprotein particles. In sporadic Alzheimer's disease patients, free sA beta42 but not sA beta40 is increased approximately 2.3-fold compared with age-matched controls, although a more marked elevation (approximately 8-fold for free sA beta40 and about 20-fold for sA beta42) is found in Down's syndrome patients. The data suggest that lipoprotein-sA beta dissociation may contribute to the influx of sA beta into the brain as a result of decreased plasma clearance
— id: 9388, year: 1999, vol: 45, page: 537, stat: Journal Article,

Abeta1-40 peptide bearing the APP693 Dutch mutation induces apoptosis in human cerebral endothelial cells
Miravalle, L; Tokuda, T; Chiarle, R; Kramer, H; Frangione, B; Ghiso, J
1999 Oct 23-28;25(1-2):2124-2124, Abstracts (Society for Neuroscience)
— id: 15838, year: 1999, vol: 25, page: 2124, stat: Journal Article,

Dual anti-amyloidogenic and anti-oxidant properties of Melatonin : a new therapy for Alzheimer's disease?
Papolla M; Chyan X; Bozner P; Soto C; Shao H; Reiter R; Brewer G; Robakis N; Zagorski M; Frangione B; Ghiso J
Alzheimer's disease and related disorders New York : Wiley, 1999,
— id: 5148, year: 1999, vol: , page: 661, stat: Chapter,

Abeta40 and Abeta42 clearance in a transgenic mouse model expressing human apoE3 and apoE4
Permanne, B.; Ji, Yong; Holtzman, D. M.; Frangione, B.; Wisniewski, T.
1999 ;25(1-2):1058-78, Abstracts (Society for Neuroscience)
— id: 97637, year: 1999, vol: 25, page: 1058, stat: Journal Article,

Beta-sheet breaker peptide inhibitor of Alzheimer's amyloidogenesis with increased blood-brain barrier permeability and resistance to proteolytic degradation in plasma
Poduslo JF; Curran GL; Kumar A; Frangione B; Soto C
1999 Jun 5;39(3):371-382, Journal of neurobiology
Short synthetic peptides homologous to the central region of Abeta but bearing proline residues as beta-sheet blockers have been shown in vitro to bind to Abeta with high affinity, partially inhibit Abeta fibrillogenesis, and redissolve preformed fibrils. While short peptides have been used extensively as therapeutic drugs in medicine, two important problems associated with their use in central nervous system diseases have to be addressed: (a) rapid proteolytic degradation in plasma, and (b) poor blood-brain barrier (BBB) permeability. Recently, we have demonstrated that the covalent modification of proteins with the naturally occurring polyamines significantly increases their permeability at the BBB. We have extended this technology to iAbeta11, an 11-residue beta-sheet breaker peptide that inhibits Abeta fibrillogenesis, by covalently modifying this peptide with the polyamine, putrescine (PUT), and evaluating its plasma pharmacokinetics and BBB permeability. After a single intravenous bolus injection in rats, both 125I-YiAbeta11 and 125I-PUT-YiAbeta11 showed rapid degradation in plasma as determined by trichloroacetic acid (TCA) precipitation and paper chromatography. By switching to the all D-enantiomers of YiAbeta11 and PUT-YiAbeta11, significant protection from degradation by proteases in rat plasma was obtained with only 1.9% and 5.7% degradation at 15 min after intravenous bolus injection, respectively. The permeability coefficient x surface area product at the BBB was five- sevenfold higher in the cortex and hippocampus for the 125I-PUT-D-YiAbeta11 compared to the 125I-D-YiAbeta11, with no significant difference in the residual plasma volume. In vitro assays showed that PUT-D-YiAbeta11 retains its ability to partially inhibit Abeta fibrillogenesis and dissolve preformed amyloid fibrils. Because of its five- to sevenfold increase in permeability at the BBB and its resistance to proteolysis in the plasma, this polyamine-modified beta-sheet breaker peptide may prove to be an effective inhibitor of amyloidogenesis in vivo and, hence, an important therapy for Alzheimer's disease
— id: 9502, year: 1999, vol: 39, page: 371, stat: Journal Article,

Melatonin abolishes the pro-aggregatory effects of apoE4 on the Alzheimer beta-protein
Poeggeler, B.; Chyan, Y.-J.; Bryant, T.; Wisniewski, T.; Frangione, B.; Ghiso, J.; Pappolla, M.
1999 ;25(1-2):1805-78, Abstracts (Society for Neuroscience)
— id: 97638, year: 1999, vol: 25, page: 1805, stat: Journal Article,

pH-dependent fibrillogenesis of a VkappaIII Bence Jones protein
Rostagno A; Vidal R; Kaplan B; Chuba J; Kumar A; Elliott JI; Frangione B; Gallo G; Ghiso J
1999 Dec;107(4):835-843, British journal of haematology
Disorders of immunoglobulin (Ig) synthesis that occur in malignant plasma-cell proliferation may result in either granular (LCDD) or fibrillar (AL) tissue deposition of light-chain monoclonal components. The structural features that govern the transition from soluble polypeptides to either fibrillar or granular conformational states remain undefined. Among the many factors presumed to play a role in these transitions the net charge of the molecule has been associated with folding conformation changes. The majority of the proteins involved in AL amyloidosis show acidic isoelectric points (pI 3.8-5.2), whereas most L chains with basic pIs deposit in granular patterns. In our studies a 12 kD VkappaIII fragment was purified as the main component of the fibrils isolated from myocardium and adipose tissue of the pericardium obtained post-mortem from an individual with systemic AL amyloidosis. An apparently identical 12 kD VL fragment with the same N-terminal sequence constituted the BJ protein present in the urine. This urinary protein exhibited strikingly cathodic electrophoretic mobility on agarose gels and lacked retention by anionic exchange chromatography matrices, indicative of a highly basic pI (>10). When it was subjected to in vitro fibril-formation experiments, the BJ protein adopted a fibrillar conformation only at acidic pHs, remaining aggregated but not fibrillar at physiological pH. The data indicate that a specific tissue deposition pattern involves not only structural properties of the protein but rather more complex mechanisms in which acidic micro-environments may contribute to the stabilization of amyloidogenic conformations
— id: 9382, year: 1999, vol: 107, page: 835, stat: Journal Article,

Cell-lysate conversion of prion protein into its protease-resistant isoform suggests the participation of a cellular chaperone
Saborio GP; Soto C; Kascsak RJ; Levy E; Kascsak R; Harris DA; Frangione B
1999 May 10;258(2):470-475, Biochemical & biophysical research communications
A conformational transition between the normal cellular prion protein (PrPC) and the beta-sheet-rich pathological isoform (PrPSc) is a central event in the pathogenesis of spongiform encephalopathies. The prion infectious agent seems to contain mainly, if not exclusively, PrPSc, which has the ability to propagate its abnormal conformation by transforming the host PrPC into the pathological isoform. We have developed an in vitro system to induce the PrPC --> PrPSc conversion by incubating a cell-lysate containing mouse PrPC with partially purified mouse PrPSc. After 48 h of incubation with a 10-fold molar excess of PrPSc, the cellular protein acquired PK-resistance resembling a PrPSc-like state. Time course experiments suggest that the conversion follows a stepwise mechanism involving kinetic intermediates. The conversion was induced by PrPSc extracted from mice infected with two different prion strains, each propagating its characteristic Western blot profile. The latter results and the fact that all the cellular components are present in the conversion reaction suggest that PrPC-PrPSc interaction is highly specific and required for the conversion. No transformation was observed under the same conditions using purified proteins without cell-lysate. However, when PrPC-depleted cell-lysate was added to the purified proteins the conversion was recovered. These findings provide direct evidence for the participation of a chaperone-like activity involved in catalyzing the conversion of PrPC into PrPSc.
— id: 6115, year: 1999, vol: 258, page: 470, stat: Journal Article,

Cell-lysate conversion of prion protein into its protease-resistant isoform indicates the participation of a cellular chaperone
Saborio, G P; Soto, C; Kascsak, R J; Levy, E; Kascsak, R; Harris, D A; Frangione, B
1999 Oct 23-28;25(1-2):41-41, Abstracts (Society for Neuroscience)
— id: 15872, year: 1999, vol: 25, page: 41, stat: Journal Article,

In vivo disassembly of cerebral amyloid-beta (Abeta) deposits in rat brain
Sigurdsson, E. M.; Permanne, B.; Soto, C.; Wisniewski, T.; Frangione, B.
1999 ;25(1-2):1805-78, Abstracts (Society for Neuroscience)
— id: 97639, year: 1999, vol: 25, page: 1805, stat: Journal Article,

beta-sheet breaker peptides prevent the formation of amyloid-beta deposits
Soto C; Sigurdsson EM; Morelli L; Kumar RA; Saborio GP; Castano EM; Frangione B
Alzheimer's disease and related disorders Chichester, NY: Wiley, 1999,
— id: 2639, year: 1999, vol: , page: ?, stat: Chapter,

Lipidation of apoE influences isoform specific interaction with Alzheimer's Abeta peptides
Tokuda, T; Calero, M; Matsubara, E; Vidal, R; Ferris, S; Smith, J; Ladu, M; Rostagno, A; Frangione, B; Ghiso, J
1999 Oct 23-28;25(1-2):1348-1348, Abstracts (Society for Neuroscience)
— id: 15846, year: 1999, vol: 25, page: 1348, stat: Journal Article,

A stop-codon mutation in the BRI gene associated with familial British dementia
Vidal R; Frangione B; Rostagno A; Mead S; Revesz T; Plant G; Ghiso J
1999 Jun 24;399(6738):776-781, Nature
Familial British dementia (FBD), previously designated familial cerebral amyloid angiopathy-British type, is an autosomal dominant disorder of undetermined origin characterized by progressive dementia, spasticity, and cerebellar ataxia, with onset at around the fifth decade of life. Cerebral amyloid angiopathy, non-neuritic and perivascular plaques and neurofibrillary tangles are the predominant pathological lesions. Here we report the identification of a unique 4K protein subunit named ABri from isolated amyloid fibrils. This highly insoluble peptide is a fragment of a putative type-II single-spanning transmembrane precursor that is encoded by a novel gene, BRI, located on chromosome 13. A single base substitution at the stop codon of this gene generates a longer open reading frame, resulting in a larger, 277-residue precursor. Release of the 34 carboxy-terminal amino acids from the mutated precursor generates the ABri amyloid subunit. The mutation creates a cutting site for the restriction enzyme XbaI, which is useful for detecting asymptomatic carriers. Antibodies against the amyloid or homologous synthetic peptides recognize both parenchymal and vascular lesions in FBD patients. A point mutation at the stop codon of BRI therefore results in the generation of the ABri peptide, which is deposited as amyloid fibrils causing neuronal disfunction and dementia
— id: 56965, year: 1999, vol: 399, page: 776, stat: Journal Article,

Somatic mutations of the L12a gene in V-kappa(1) light chain deposition disease: potential effects on aberrant protein conformation and deposition
Vidal R; Goni F; Stevens F; Aucouturier P; Kumar A; Frangione B; Ghiso J; Gallo G
1999 Dec;155(6):2009-2017, American journal of pathology
Light chain deposition disease (LCDD) and light chain amyloidosis (AL) are disorders of monoclonal immunoglobulin deposition in which normally soluble serum precursors form insoluble deposits in tissues. A common feature in both is the clonal proliferation of B-cells that produce pathogenic light chains. However, the deposits in LCDD differ from those in AL in that they are ultrastructurally granular rather than fibrillar and do not bind Congo red or colocalize with amyloid P component or apolipoprotein E. The reason(s) for their differences are unknown but are likely multifactorial and related to their protein conformation and their interaction with other molecules and tissue factors in the microenvironment. Knowledge of the primary structure of the light chains in LCDD is very limited. In the present study two new kappa(1) light chains from patients with LCDD are described and compared to seven other reported kappa-LCDD proteins. The N-terminal amino acid sequences of light chain GLA extracted from the renal biopsy and light chain CHO from myocardial tissue were each identical to the respective light chains isolated from the urines and to the V-region amino acid sequences translated from the cloned cDNAs obtained from bone marrow cells. The germline V-region sequences, determined from the genomic DNA in both and in MCM, a previously reported kappa(1) LCDD light chain, were identical and related to the L12a germline gene. The expressed light chains in all three exhibit amino acid substitutions that arise from somatic mutation and result in increased hydrophobicity with the potential for protein destabilization and disordered conformation
— id: 9383, year: 1999, vol: 155, page: 2009, stat: Journal Article,

Biotechnological production of A? peptides
Vidal R; Shao X; Ghiso J; Gorevic P; Frangione B
Alzheimer's disease and related disorders New York : Wiley, 1999,
— id: 5147, year: 1999, vol: , page: 723, stat: Chapter,

Nomenclature of amyloid fibril proteins. Report from the meeting of the International Nomenclature Committee on Amyloidosis, August 8-9, 1998. Part 1
Westermark P; Araki S; Benson MD; Cohen AS; Frangione B; Masters CL; Saraiva MJ; Sipe JD; Husby G; Kyle RA; Selkoe D
1999 Mar;6(1):63-66, Amyloid
— id: 9504, year: 1999, vol: 6, page: 63, stat: Journal Article,

Amyloid: chemical and molecular considerations
Wisniewski T; Frangione B
An atlas of Alzheimer's disease New York : Parthenon Publishing, 1999,
— id: 4977, year: 1999, vol: , page: 109, stat: Chapter,

Neurovascular interactions of Alzheimer's amyloid ? peptide with apolipoproteins J and E
Zlokovic B; Frangione B; Ghiso J
Clusterin in normal brain functions and during neurodegeneration Austin TX : RG Landes, 1999,
— id: 5149, year: 1999, vol: , page: 71, stat: Chapter,

Alzheimer's beta-amyloid vasoactivity: identification of a novel beta-amyloid conformational intermediate
Crawford F; Soto C; Suo Z; Fang C; Parker T; Sawar A; Frangione B; Mullan M
1998 Oct 9;436(3):445-448, FEBS letters
The beta-amyloid (A beta) peptide has previously been shown to enhance phenylephrine or endothelin-1 induced constriction of aortic rings in vitro. The characteristics of A beta vasoactivity (dose, fragment length, timing) suggest that the mechanism is distinct from A beta cytotoxicity. To identify which properties of A beta determine its biological activity on vessels, we investigated a number of A beta analogues and fragments, individually and in combination, including those that are known to be associated with Alzheimer's disease (A beta(1-42)) and hereditary cerebral hemorrhage with amyloidosis--Dutch type (A beta(22Q)(1-40)). The vasoactivity appears to be related to the conformation adopted by the peptide in solution. The beta-pleated sheet rich A beta(1-42) and A beta(22Q)(1-40) were each less vasoactive than the mainly random coil wild type A beta(1-40). However, the most vasoactive A beta peptides were combinations which contain mixtures of random coil and beta-sheet structure. The finding that peptides containing low or high levels of beta-pleated conformation are less vasoactive than those containing intermediate amounts of this structural motif allows us to propose the existence of a transitional form between random coil and beta-pleated that is the vasoactive species of A beta. This is the first time that A beta conformational intermediates have been identified and a biological activity associated with them
— id: 57129, year: 1998, vol: 436, page: 445, stat: Journal Article,

Antibodies directed to the carboxyl terminus of amyloid beta peptides recognize sequence epitopes and distinct immunoreactive deposits in Alzheimer's disease brain
Jimenez-Huete A; Alfonso P; Soto C; Albar P; Rabano A; Ghiso J; Frangione B; Mendez E
1998 ;1:41-48, Alzheimer's reports
— id: 102367, year: 1998, vol: 1, page: 41, stat: Journal Article,

Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues
Jimenez-Huete A; Lievens PM; Vidal R; Piccardo P; Ghetti B; Tagliavini F; Frangione B; Prelli F
1998 Nov;153(5):1561-1572, American journal of pathology
We have investigated the proteolytic cleavage of the cellular (PrPC) and pathological (PrPSc) isoforms of the human prion protein (PrP) in normal and prion-affected brains and in tonsils and platelets from neurologically intact individuals. The various PrP species were resolved after deglycosylation according to their electrophoretic mobility, immunoreactivity, Sarkosyl solubility, and, as a novel approach, resistance to endogenous proteases. First, our data show that PrPC proteolysis in brain originates amino-truncated peptides of 21 to 22 and 18 (C1) kd that are similar in different regions and are not modified by the PrP codon 129 genotype, a polymorphism that affects the expression of prion disorders. Second, this proteolytic cleavage of PrPC in brain is blocked by inhibitors of metalloproteases. Third, differences in PrPC proteolysis, and probably in Asn glycosylation and glycosylphosphatidylinositol anchor composition, exist between neural and non-neural tissues. Fourth, protease-resistant PrPSc cores in sporadic Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker F198S disease brains all have an intact C1 cleavage site (Met111-His112), which precludes disruption of a domain associated with toxicity and fibrillogenesis. Fifth, the profile of endogenous proteolytic PrPSc peptides is characteristic of each disorder studied, thus permitting the molecular classification of these prion diseases without the use of proteinase K and even a recognition of PrPSc heterogeneity within type 2 CJD patients having different codon 129 genotype and neuropathological phenotype. This does not exclude the role of additional factors in phenotypic expression; in particular, differences in glycosylation that may be especially relevant in the new variant CJD. Proteolytic processing of PrP may play an important role in the neurotropism and phenotypic expression of prion diseases, but it does not appear to participate in disease susceptibility
— id: 7624, year: 1998, vol: 153, page: 1561, stat: Journal Article,

HB-GAM, a novel amyloid associated protein, is present in prion related disorders and other cerebral amyloidoses
Lalowski M; Baumann M; Rauvala H; Frangione B; Wisniewski T
Progress in Alzheimer's and Parkinson's diseases New York : Plenum, 1998,
— id: 4982, year: 1998, vol: , page: 121, stat: Chapter,

Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer
Mackic JB; Stins M; McComb JG; Calero M; Ghiso J; Kim KS; Yan SD; Stern D; Schmidt AM; Frangione B; Zlokovic BV
1998 Aug 15;102(4):734-743, Journal of clinical investigation
A soluble monomeric form of Alzheimer's amyloid-beta (1-40) peptide (sAbeta1-40) is present in the circulation and could contribute to neurotoxicity if it crosses the brain capillary endothelium, which comprises the blood-brain barrier (BBB) in vivo. This study characterizes endothelial binding and transcytosis of a synthetic peptide homologous to human sAbeta1-40 using an in vitro model of human BBB. 125I-sAbeta1-40 binding to the brain microvascular endothelial cell monolayer was time dependent, polarized to the apical side, and saturable with high- and low-affinity dissociation constants of 7.8+/-1.2 and 52.8+/-6.2 nM, respectively. Binding of 125I-sAbeta1-40 was inhibited by anti-RAGE (receptor for advanced glycation end products) antibody (63%) and by acetylated low density lipoproteins (33%). Consistent with these data, transfected cultured cells overexpressing RAGE or macrophage scavenger receptor (SR), type A, displayed binding and internalization of 125I-sAbeta1-40. The internalized peptide remains intact > 94%. Transcytosis of 125I-sAbeta1-40 was time and temperature dependent, asymmetrical from the apical to basolateral side, saturable with a Michaelis constant of 45+/-9 nM, and partially sensitive to RAGE blockade (36%) but not to SR blockade. We conclude that RAGE and SR mediate binding of sAbeta1-40 at the apical side of human BBB, and that RAGE is also involved in sAbeta1-40 transcytosis
— id: 7669, year: 1998, vol: 102, page: 734, stat: Journal Article,

Cerebrovascular accumulation and increased blood-brain barrier permeability to circulating Alzheimer's amyloid beta peptide in aged squirrel monkey with cerebral amyloid angiopathy
Mackic JB; Weiss MH; Miao W; Kirkman E; Ghiso J; Calero M; Bading J; Frangione B; Zlokovic BV
1998 Jan;70(1):210-215, Journal of neurochemistry
Senescent squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Cerebrovascular sequestration and blood-brain barrier (BBB) permeability to 121I-amyloid beta(1-40) synthetic peptide (sA beta(1-40)) were studied in adult versus aged squirrel monkey 1 h after a single intravenous injection. In aged monkey, the half-time of elimination of sA beta(1-40), t(1/2)e, was prolonged by 0.6 h, the systemic clearance, ClSS, was reduced from 1.8 to 1.1 ml/min/kg, and the mean residence time of intact peptide in the circulation was increased by 1 h (45%). In adult monkey, cerebrovascular sequestration of intact sA beta(1-40) was significant, and the BBB permeability was 18.6-fold higher than for inulin. In aged monkey, the sequestration of intact sA beta(1-40) by cortical and leptomeningeal microvessels and the BBB permeability were increased by 5.9, 1.8-, and 2.1-fold, respectively, in the presence of an unchanged barrier to inulin. In brain parenchyma of aged animals, 76.1% of circulating sA beta(1-40) remained intact versus 45.7% in adult. We conclude that multiple age-related systemic effects, i.e., reduced body elimination and systemic clearance of sA beta(1-40), and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendothelial transport and microvascular accumulation of blood-borne sA beta(1-40), and reduced brain metabolism to enhance the development of CAA
— id: 57200, year: 1998, vol: 70, page: 210, stat: Journal Article,

Inhibition of Alzheimer beta-fibrillogenesis by melatonin
Pappolla M; Bozner P; Soto C; Shao H; Robakis NK; Zagorski M; Frangione B; Ghiso J
1998 Mar 27;273(13):7185-7188, Journal of biological chemistry
It is generally postulated that the amyloid beta protein (Abeta) plays a central role in the progressive neurodegeneration observed in Alzheimer's disease. Important pathologic properties of this protein, such as neurotoxicity and resistance to proteolytic degradation, depend on the ability of Abeta to form beta-sheet structures or amyloid fibrils. We report that melatonin, a hormone recently found to protect neurons against Abeta toxicity, interacts with Abeta1-40 and Abeta1-42 and inhibits the progressive formation of beta-sheets and amyloid fibrils. These interactions between melatonin and the amyloid peptides were demonstrated by circular dichroism and electron microscopy for Abeta1-40 and Abeta1-42 and by nuclear magnetic resonance spectroscopy for Abeta1-40. Inhibition of beta-sheets and fibrils could not be accomplished in control experiments when a free radical scavenger or a melatonin analog were substituted for melatonin under otherwise identical conditions. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease
— id: 9390, year: 1998, vol: 273, page: 7185, stat: Journal Article,

beta-sheet breaker peptides as potential therapy for Alzheimer's disease
Sigurdsson, EM; Morelli, L; Kumar, RA; Castano, EM; Frangione, B; Soto, C
1998 NOV ;1(1):S35-S36, Alzheimer's reports
— id: 98326, year: 1998, vol: 1, page: S35, stat: Journal Article,

Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer's therapy [see comments]
Soto C; Sigurdsson EM; Morelli L; Kumar RA; Castano EM; Frangione B
1998 Jul;4(7):822-826, Nature medicine
Inhibition of cerebral amyloid beta-protein deposition seems to be an important target for Alzheimer's disease therapy. Amyloidogenesis could be inhibited by short synthetic peptides designed as beta-sheet breakers. Here we demonstrate a 5-residue peptide that inhibits amyloid beta-protein fibrillogenesis, disassembles preformed fibrils in vitro and prevents neuronal death induced by fibrils in cell culture. In addition, the beta-sheet breaker peptide significantly reduces amyloid beta-protein deposition in vivo and completely blocks the formation of amyloid fibrils in a rat brain model of amyloidosis. These findings may provide the basis for a new therapeutic approach to prevent amyloidosis in Alzheimer's disease
— id: 7803, year: 1998, vol: 4, page: 822, stat: Journal Article,

The prionoses and other conformational disorders
Wisniewski T; Aucouturier P; Soto C; Frangione B
1998 Sep;5(3):212-224, Amyloid
The basic pathogenesis of numerous neurodegenerative disorders is now thought to be related to abnormal protein conformation. The common theme in all these diseases is the conversion of a normal cellular and/or circulating protein into an insoluble, aggregated, beta-sheet rich form which is deposited in the brain, sometimes in the form of amyloid. These deposits are toxic and produce neuronal dysfunction and death. The most common of these illnesses is Alzheimer's disease (AD), in which a central event is the conversion of the normal soluble amyloid beta (sA beta) peptide to amyloid beta (A beta) within neuritic plaques and cerebral vessels. A unique category of the conformational conditions are prion related diseases (or prionoses), where the etiology is thought to be related to conversion of the normal prion protein, PrPC, into an infectious and pathogenic form, PrPSc. In the case of AD and the prionoses, the conformational change can be influenced by the presence of mutations in various gene products, as well as by chaperone proteins. Apolipoprotein E is thought to act as such a chaperone protein in AD; however, among the prionoses such a protein has been hypothesized to exist only by indirect evidence and is called 'protein X'. Our growing understanding of the mechanisms involved in this category of diseases, raises the possibility of therapeutic approaches based directly on the prevention and reversal of pathologic protein conformation
— id: 7855, year: 1998, vol: 5, page: 212, stat: Journal Article,

A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years
Wisniewski T; Dowjat WK; Buxbaum JD; Khorkova O; Efthimiopoulos S; Kulczycki J; Lojkowska W; Wegiel J; Wisniewski HM; Frangione B
1998 Jan 26;9(2):217-221, Neuroreport
The majority of early-onset familial Alzheimer's disease (FAD) is associated with mutations in the presenilin-1 (PS1) gene. We describe a novel Polish PS1 mutation of Pro117Leu, associated with the earliest average age of onset and death so far reported in a PS-linked, FAD kindred. Human kidney 293 and mouse neuroblastoma N2a cells were stably transfected with wild-type and PS1 P117L. There was a significant increase in the amyloid beta42/40 ratio in the N2a P117L PS1 transfected cells compared with N2a transfected with wild-type PS1. What role PS has in the pathogenesis of AD remains to be determined, however, the severity of the clinical picture associated with this PS1 mutation stresses the importance of presenilin
— id: 7856, year: 1998, vol: 9, page: 217, stat: Journal Article,

A novel Polish presenilin-1 mutation (P117L) associated with a very early onset of familial Alzheimer's disease
Wisniewski, T; Dowjat, WK; Buxbaum, JD; Kulczycki, J; Lojkowska, W; Wegiel, J; Wisniewski, HM; Frangione, B
1998 ;50(4):P04107-221, Neurology
— id: 97627, year: 1998, vol: 50, page: P04107, stat: Journal Article,

Biology of A beta amyloid in Alzheimer's disease (vol 4, pg 313, 1997)
Wisniewski, T; Ghiso, J; Frangione, B
1998 ;5(1):65-65, Neurobiology of disease
— id: 97597, year: 1998, vol: 5, page: 65, stat: Journal Article,

Proteinases secreted by Fasciola hepatica degrade extracellular matrix and basement membrane components
Berasain P; Goni F; McGonigle S; Dowd A; Dalton JP; Frangione B; Carmona C
1997 Feb;83(1):1-5, Journal of parasitology
The invasive stages of the parasitic trematode Fasciola hepatica release proteinases into the medium in which they are maintained. In this study, we investigated the interaction of F. hepatica excretory/secretory (E/S) products and 2 cysteine proteinases (CL1 and CL2) purified from these products with extracellular matrix and basement membrane macromolecules. Fasciola hepatica E/S products contained collagenolytic activity on fibrillar types I and III collagen as well as basement membrane type IV collagen. CL1 and CL2 were capable of degrading acid-soluble type III and type IV collagen but not insoluble type I collagen. In contrast, neither the E/S products nor the purified CL1 and CL2 showed elastinolytic activity. Fibronectin and laminin were degraded by E/S products and by CL1 and CL2. Sequence analysis of fibronectin degradation products showed that the fragments obtained corresponded to complete biologically active domains. These results indicate that the cysteine proteinases secreted by F. hepatica may be involved in the process of tissue invasion by the parasite
— id: 9506, year: 1997, vol: 83, page: 1, stat: Journal Article,

Immunoglobulin lambda light chains are the precursors of ureteral localized amyloidosis: a micromethod for extraction of amyloid
Castano, EM; Prelli, F; Morelli, L; Avagnina, A; Kahn, A; Frangione, B
1997 DEC ;4(4):253-258, Amyloid
We present the biochemical characterization of two amyloid proteins, including their partial amino terminal sequence, isolated from localized forms of ureteral amyloidosis. The major component of amyloid NAV, extracted from milligram quantities of biopsy tissue, had a molecular mass of 16 kDa and the 20 first amino acids showed homology to immunoglobulin (Ig) light chain of the subgroup lambda II. In addition, amyloid P component co-purified with amyloid NAV as determined by Western blot analysis. Amyloid MAI was extracted from formalin fixed, paraffin embedded tissue. It had a molecular mass of 14 kDa and its amino terminal sequence (17 steps) revealed homology to Ig light chain of the subgroup lambda III. These results provide additional evidence for the association between amyloidogenic Ig light chains and localized, tumor-like forms of amyloidosis. Moreover the two simple methods presented here may facilitate the characterization of amyloid proteins from small samples of frozen tissue and rare specimens stored in paraffin blocks
— id: 53591, year: 1997, vol: 4, page: 253, stat: Journal Article,

Vasoactivity of the Alzheimer A beta peptides and fibrillogenic potential
Crawford, F; Suo, ZM; Fang, CH; Frangione, B; Mullan, M
1997 OCT ;61(4):1929-2347, American journal of human genetics
— id: 98351, year: 1997, vol: 61, page: 1929, stat: Journal Article,

Alzheimer's soluble amyloid beta is a normal component of human urine
Ghiso J; Calero M; Matsubara E; Governale S; Chuba J; Beavis R; Wisniewski T; Frangione B
1997 May 12;408(1):105-108, FEBS letters
Soluble A beta (Sa beta) is normally present at a low concentration in human plasma and cerebrospinal fluid. Although the factors involved in the regulation of Sa beta plasma levels are still unknown, we have explored its excretion in the urine as one of the possible homeostatic mechanisms. The presence of Sa beta in the urine was investigated via immunoprecipitation experiments with anti-A beta antibodies followed by detection and identification by immunoblot, MALDI mass spectrometry and sequence analysis. Soluble A beta (4.3 kDa) immunoreactivity was present in the urine of normal donors, Down's syndrome individuals as well as in patients with renal disorders exhibiting glomerular or mixed proteinuria. Edman degradation of the immunoprecipitated material yielded the intact A beta N-terminus and mass spectra analysis indicated the existence of a major component at mlz 4327, corresponding to the molecular mass of A beta1-40. Semiquantitative data obtained from the immunoprecipitation experiments indicate that under normal conditions the daily excretion of intact Sa beta in the urine represents less than 1% of the circulating pool
— id: 7153, year: 1997, vol: 408, page: 105, stat: Journal Article,

In vivo blood-brain barrier uptake of Alzheimer's A? peptides in guinea pigs : evidence for vascular sequestration of A?1-40 (but not A?1-42)
Ghiso J; Martel C; Mackic J; McComb JG; Frangione B; Zlokovic B
Alzheimer's disease : biology, diagnosis, and therapeutics New York : Wiley, 1997,
— id: 5146, year: 1997, vol: , page: 375, stat: Chapter,

Amino-terminal identity of co-existent amyloid and non-amyloid immunoglobulin kappa light chain deposits. A human disease to study alterations of protein conformation
Kaplan B; Vidal R; Kumar A; Ghiso J; Frangione B; Gallo G
1997 Dec;110(3):472-478, Clinical & experimental immunology
Tissue deposition of monoclonal immunoglobulin light chains is a serious complication in some patients with B cell proliferative disorders. The deposits are typically fibrillar and Congophilic in amyloid (AL) and non-fibrillar and Congophobic in light chain deposition disease (LCDD), and rarely coexist in the same patient. From post-mortem tissue of an individual with fibrillar and non-fibrillar kappa light chain deposits in different sites, we separately extracted and analysed biochemically and immunochemically the non-amyloid deposits from isolated glomeruli, the amyloid from isolated renal arteries and the amyloid from myocardium in which the only deposits were amyloid restricted to mural arteries. Western blotting analysis of both the extracted amyloid and the non-amyloid deposits demonstrated 25-kD bands immunoreactive with anti-kappa antibody, and the identity of the N-terminal amino acid sequences that belong to the variable region kappaIV light chain subgroup. This is the first human disease in which antigenically similar but morphologically different deposits have been separately biochemically analysed. We propose that combined LCDD and AL is an ideal human disease to study the relationships and the factors that influence the conversion of non-amyloidogenic to amyloidogenic conformations
— id: 7942, year: 1997, vol: 110, page: 472, stat: Journal Article,

Isoform-specific effects of apolipoproteins E2, E3, and E4 on cerebral capillary sequestration and blood-brain barrier transport of circulating Alzheimer's amyloid beta
Martel CL; Mackic JB; Matsubara E; Governale S; Miguel C; Miao W; McComb JG; Frangione B; Ghiso J; Zlokovic BV
1997 Nov;69(5):1995-2004, Journal of neurochemistry
Cerebral capillary sequestration and blood-brain barrier (BBB) permeability to apolipoproteins E2 (apoE2), E3 (apoE3), and E4 (apoE4) and to their complexes with sA beta(1-40), a peptide homologous to the major form of soluble Alzheimer's amyloid beta, were studied in perfused guinea pig brain. Cerebrovascular uptake of three apoE isoforms was low, their blood-to-brain transport undetectable, but uptake by the choroid plexus significant. Binding of all three isoforms to sA beta(1-40) in vitro was similar with a K(D) between 11.8 and 12.9 nM. Transport into brain parenchyma and sequestration by BBB and choroid plexus were negligible for sA beta(1-40)-apoE2 and sA beta(1-40)-apoE3, but significant for sA beta(1-40)-apoE4. After 10 min, 85% of sA beta(1-40)-apoE4 taken up at the BBB remained as intact complex, whereas free sA beta(1-40) was 51% degraded. Circulating apoE isoforms have contrasting effects on cerebral capillary uptake of and BBB permeability of sA beta. ApoE2 and apoE3 completely prevent cerebral capillary sequestration and blood-to-brain transport of sA beta(1-40). Conversely, apoE4, by entering brain microvessels and parenchyma as a stable complex with sA beta, reduces peptide degradation and may predispose to cerebrovascular and possibly enhance parenchymal amyloid formation under pathological conditions
— id: 9391, year: 1997, vol: 69, page: 1995, stat: Journal Article,

Transport of apolipoproteins E and J at the blood-brain barrier - Relevance to Alzheimer's disease
Martel, CL; Ghiso, J; Frangione, B; Zlokovic, BV
1997 JAN-FEB ;7(1):28-36, S.T.P. pharma pratiques : techniques reglementations
It has been shown that the blood-brain barrier regulates uptake of apolipoprotein E and apolipoprotein J, and of their complexes with soluble amyloid beta(1-40), a synthetic peptide homologous to the major form of soluble Alzheimer's amyloid beta peptide. Apolipoprotein E isoforms E3 and E4 do not enter. brain parenchyma, and exhibit minimal sequestration by cerebral capillaries. There is negligible brain uptake and sequestration of the soluble amyloid beta(1-40)-apolipoprotein E3 complex, but there is moderate uptake of intact soluble amyloid beta(1-40)-apolipoprotein E4 which is mediated by an as yet unknown mechanism. Both apolipoprotein J and soluble amyloid beta(1-40)-apolipoprotein J exhibit a remarkable cerebrovascular permeability which appears to be mediated by the glycoprotein 330 (megalin) receptor. It is therefore suggested that blood-brain barrier transport of apolipoproteins complexed with amyloid beta may play a role in either preventing (in the case of apolipoproteins J and E3) or enhancing (in the case of apolipoprotein E4) the formation of amyloid deposits in cerebral microvessels and brain parenchyma under certain pathological conditions
— id: 53196, year: 1997, vol: 7, page: 28, stat: Journal Article,

C for T substitution at codon 108: The first identified silent mutation in the transthyretin gene
Palha, JA; Moreira, P; Wisniewski, T; Frangione, B; Saraiva, MJ
1997 ;4(1):52-53, Amyloid
Transthyretin (TTR) is a 55 kDA tetrameric protein synthesized by the liver and the choroid plexus that binds thyroxine and retinol-binding protein. More than fifty mutations have been identified in the TTR gene, the majority of them associated with hereditary amyloidosis.(1) This study reveals the first silent mutation on the TTR gene:Ala108. $$:
— id: 97594, year: 1997, vol: 4, page: 52, stat: Journal Article,

Inhibition of Alzheimer's ?-amyloid fibril formation
Pappolla M; Bozner P; Soto C; Zagorski M; Shao H; Frangione B; Ghiso J
1997 ;1:?-?, Emerging therapeutic targets
— id: 102368, year: 1997, vol: 1, page: ?, stat: Journal Article,

Detection of apolipoprotein E/dimeric soluble amyloid beta complexes in Alzheimer's disease brain supernatants
Permanne B; Perez C; Soto C; Frangione B; Wisniewski T
1997 Nov 26;240(3):715-720, Biochemical & biophysical research communications
The inheritance of the apolipoprotein (apo) E4 allele is an important risk factor for late-onset Alzheimer's disease (AD). A major component of the Alzheimer's disease neuritic plaques is amyloid beta (A beta). We previously identified apoE/A beta complexes within neuritic plaques (1). It was not known if this interaction takes place before or after A beta peptides become incorporated into neuritic plaques. To address this question we sought evidence of apoE complexes with brain soluble A beta peptides in AD and control patients. In addition, numerous proteins have been shown to bind A beta peptides in vitro. It is not know if any of these bind brain sA beta in vivo. We found evidence for the presence of apoE/dimeric sA beta complexes in the AD brain and could not detect complexes with other A beta peptide binding proteins. The binding of sA beta to apoE may be one factor influencing its clearance from the brain and/or its conformational state
— id: 9505, year: 1997, vol: 240, page: 715, stat: Journal Article,

Soluble amyloid beta/apolipoprotein E complexes in the Alzheimer brain
Permanne, B.; Perez, C.; Soto, C.; Frangione, B.; Wisniewski, T.
1997 ;23(1-2):538-53, Abstracts (Society for Neuroscience)
— id: 97640, year: 1997, vol: 23, page: 538, stat: Journal Article,

Presenilin-1 is associated with Alzheimer's disease amyloid
Wisniewski T; Dowjat WK; Permanne B; Palha J; Kumar A; Gallo G; Frangione B
1997 Aug;151(2):601-610, American journal of pathology
Mutations in presenilin (PS)-1 and -2, located on chromosome 14 and 1 respectively, are the major association with early-onset familial Alzheimer's disease (FAD). FAD has also been linked to mutations in the amyloid beta precursor protein (beta PP), and the presence of the apolipoprotein E4 allele is a risk factor for late-onset AD. The role of PS in FAD and in sporadic AD is unclear. We previously reported the presence of a PS-1 carboxyl-terminal epitope in neuritic plaques (Wisniewski T, Palha JA, Ghiso J, Frangione B: S182 protein in Alzheimer's disease neuritic plaques. Lancet 1995, 346:1366). In the present study, we examined a number of biochemically different cerebral and systemic amyloidoses, finding the PS-1 carboxy epitope only in association with amyloid beta (A beta) lesions. We confirm the presence of this epitope ultrastructurally in neuritic plaques. In addition, biochemical and amino acid sequence data are presented for an association of the 18-kd carboxy fragment of PS-1 with neuritic plaques with a start at residue 300. Three of the proteins with linkage to AD have now been found as components of neuritic plaques. It remains to be determined whether all of these proteins are involved in the same or different pathological pathway(s) and which of these proteins is the most important for the common, late-onset form of AD
— id: 7282, year: 1997, vol: 151, page: 601, stat: Journal Article,

Biology of A beta amyloid in Alzheimer's disease
Wisniewski T; Ghiso J; Frangione B
1997 ;4(5):313-328, Neurobiology of disease
The genetic associations with the pathological features of AD are diverse: A rapidly growing number of mutations in presenilin 1 and 2 on chromosomes 14 and 1, respectively, are found in many early-onset FAD patients (Lendon et al., 1997). In addition, beta PP mutations are found in a small percentage of early-onset FAD kindreds. The apoE4 allele on chromosome 19 is associated with the presence of the most common form of AD, sporadic AD (Wisniewski & Frangione, 1992; Namba et al., 1991). However, it is clear that other proteins are also involved in the pathogenesis of AD, since some early-onset FAD kindreds do not have linkage to PS1, PS2, apoE, or beta PP, while at least 50% of late-onset AD is unrelated to apoE. Other proteins which have been implicated in the formation of senile plaques, but so far are not known to have any genetic linkage to AD, include proteoglycans (Snow et al., 1987), apoA1 (Wisniewski et al., 1995a), alpha 1-antichymotrypsin (Abraham et al., 1988), HB-GAM (Wisniewski et al., 1996a), complement components (McGeer & Rogers, 1992), acetylcholinesterase (Friede, 1965), and NAC (Ueda et al., 1993). Which of these proteins will be the most important for the etiology of the most common form of AD, late-onset sporadic AD, remains an open question. Three of the genes which are now known to be linked to AD, including PS1, beta PP, and apoE, have been established immunohistochemically and biochemically to be components of senile plaques (see Fig. 1). This raises at least two possibilities: either each of these proteins is part of one pathway with A beta-related amyloid formation as a final causative pathogenic event or amyloid deposition in AD is a reactive process related to dysfunction of a number of different CNS proteins. Whether or not amyloid formation is directly causative in the pathogenesis of AD, current data suggest that new therapeutic approaches which may inhibit the aggregation and/or the conformational change of sA beta to A beta fibrils (Soto et al., 1996) have the greatest likelihood to make a significant impact on controlling amyloid accumulation in AD
— id: 7854, year: 1997, vol: 4, page: 313, stat: Journal Article,

A novel presenilin-1 mutation at codon 117 (P117L) in a Polish familial Alzheimer's disease kindred
Wisniewski, T.; Dowjat, K.; Kulczycki, J.; Wisniewski, H. M.; Wegiel, J.; Frangione, B.
1997 ;23(1-2):825-80, Abstracts (Society for Neuroscience)
— id: 97621, year: 1997, vol: 23, page: 825, stat: Journal Article,

The four genes linked to Alzheimer's Disease are expressed in neuritic plaques
Wisniewski, T.; Lalowski, M.; Dowjat, K.; Frangione, B.
1997 ;45(3):238A-80, Journal of investigative medicine
— id: 97622, year: 1997, vol: 45, page: 238A, stat: Journal Article,

The length of amyloid-beta in hereditary cerebral hemorrhage with amyloidosis, Dutch type. Implications for the role of amyloid-beta 1-42 in Alzheimer's disease
Castano EM; Prelli F; Soto C; Beavis R; Matsubara E; Shoji M; Frangione B
1996 Dec 13;271(50):32185-32191, Journal of biological chemistry
In hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), a genetic variant (E22Q) of amyloid beta (Abeta) accumulates predominantly in the small vessels of leptomeninges and cerebral cortex, leading to fatal strokes in the fifth or sixth decade of life. Abeta deposition in the neuropil occurs mainly in the form of preamyloid, Congo red negative deposits, while mature neuritic plaques and neurofibrillary tangles, hallmark lesions in Alzheimer's disease (AD), are characteristically absent. A recent hypothesis regarding the pathogenesis of AD states that Abeta extending to residues 42-43 (as opposed to shorter species) can seed amyloid formation and trigger the development of neuritic plaques followed by neuronal damage in AD. We characterized biochemically and immunohistochemically Abeta from three cases of HCHWA-D to determine its length in vascular and parenchymal deposits. Mass spectrometry of formic acid-soluble amyloid, purified by size-exclusion gel chromatography, showed that Abeta 1-40 and its carboxyl-terminal truncated derivatives were the predominant forms in leptomeningeal and cortical vessels. Abeta 1-42 was a minor component in these amyloid extracts. Immunohistochemistry with antibodies S40 and S42, specific for Abeta ending at Val-40 or Ala-42, respectively, were consistent with the biochemical data from vascular amyloid. In addition, parenchymal preamyloid lesions were specifically stained with S42 and were not labeled by S40, in agreement with the pattern reported for AD, Down's syndrome, and aged dogs. Our results suggest that in HCHWA-D the carboxyl-terminal Abeta heterogeneity is due to limited proteolysis in vivo. Moreover, they suggest that Abeta species ending at Ala-42 may not be critical for the seeding of amyloid formation and the development of AD-like neuritic changes
— id: 9508, year: 1996, vol: 271, page: 32185, stat: Journal Article,

Clearance of Alzheimer's soluble beta-peptide from ventricular cerebrospinal fluid into blood
Fenstermacher, J; Strazielle, N; GhersiEgea, JF; Ghiso, J; Dehouck, MP; Patlak, C; Frangione, B; Gorevic, P
1996 MAR 8 ;10(3):3912-3912, FASEB journal
— id: 98397, year: 1996, vol: 10, page: 3912, stat: Journal Article,

Chaperoning amyloid in Alzheimer's disease: the art of avoiding sticky situations?
Frangione B; Castano EM; Prelli F; Soto C; Ghiso J; Wisniewski T
Apolipoprotein E and Alzheimer's disease Berlin : Springer, 1996,
— id: 4976, year: 1996, vol: , page: 151, stat: Chapter,

Apolipoprotein E and amyloidogenesis
Frangione B; Castano EM; Wisniewski T; Ghiso J; Prelli F; Vidal R
1996 ;199:132-141, CIBA Foundation symposium
Alzheimer's amyloid beta-protein (A beta) is a modified, pathogenic form of a constitutive host protein, soluble amyloid beta-protein (sA beta). Both are conformational isomers encoded by the gene for the beta-amyloid precursor protein (APP), located on chromosome 21. sA beta and A beta have identical sequence but are thought to differ in their secondary structure and physicochemical properties, hence they are conformational isomers. sA beta is easily degraded, while A beta is particularly resistant. A beta has a high beta-pleated sheet content, while sA beta is thought to be more random-coil and/or alpha-helical. A beta, unlike sA beta, adopts an amyloidogenic conformation, forms aggregates and gives rise to fibrils. Most early-onset forms of Alzheimer's disease (AD) have been linked to mutations of the presenilin 1, presenilin 2 or APP genes, located on chromosomes 14, 1 and 21, respectively. Their relationship to amyloidogenesis is being investigated. On the other hand, the major risk factor for the most common form, sporadic and familial late-onset AD, is the presence of the apoE epsilon 4 allele. Recent studies have shown that a 10 kDa C-terminal fragment of apoE is complexed to A beta in neuritic plaques and that apoE isoforms can modulate amyloid formation in vitro. Moreover, thrombin cleavage of apoE generates a similar C-terminal fragment that can form amyloid-like fibrils. Thus neuritic plaques may contain both A beta and apoE amyloid fibrils. AD can be neuropathologically defined by the presence of several interacting proteins that can adopt an amyloidogenic conformation. This has led us to hypothesize that in AD, amyloidosis may be reactive rather than causative
— id: 9396, year: 1996, vol: 199, page: 132, stat: Journal Article,

Light chain cardiomyopathy. Structural analysis of the light chain tissue deposits [see comments]
Gallo G; Goni F; Boctor F; Vidal R; Kumar A; Stevens FJ; Frangione B; Ghiso J
1996 May;148(5):1397-1406, American journal of pathology
Cardiomyopathy due to monoclonal light chain deposits is a complication of plasma cell disorders. The deposits may be either fibrillar as in light chain amyloid or nonfibrillar as in light chain deposition disease. The reasons for these structural differences are still unknown. We characterized the myocardial deposits by immunohistochemical examination of sections and extraction and biochemical analysis of the tissue deposits in a patient (MCM) who died of myeloma and systemic light chain deposition disease. Amino acid sequence analysis of the extracted nonfibrillar MCM kappa-light chain reveals that it belongs to the L12a germline subset of the kappa(I) protein and contains five distinctive amino acid substitutions (three in the framework region III and two in the complementarity-determining region III) that have not been reported previously in the same positions in other kappa(I) light chains. The theoretically determined isoelectric point (pI 8.21) of the MCM light chain is high compared with the low isoelectric point of other Bence Jones proteins from subjects without light chain deposition disease. The diffuse binding to basement membranes and the high isoelectric point of the MCM kappa-light chain suggest electrostatic interaction as a possible mechanism of tissue deposition. The spatial locations of the five distinctive residues and a sixth rare substitution of the MCM protein modeled on the backbone structure of REI, a kappa(I)-soluble Bence Jones light chain of known three-dimensional structure, may be responsible for protein destabilization, partial unfolding, and aggregation leading to tissue deposition
— id: 9393, year: 1996, vol: 148, page: 1397, stat: Journal Article,

Fate of cerebrospinal fluid-borne amyloid beta-peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries
Ghersi-Egea JF; Gorevic PD; Ghiso J; Frangione B; Patlak CS; Fenstermacher JD
1996 Aug;67(2):880-883, Journal of neurochemistry
In Alzheimer's disease, the neuritic or senile amyloid plaques in hippocampus and association cortex, the diffuse plaques in brain areas such as the cerebellum and sensorimotor cortex, and the amyloid deposits in the walls of pial and parenchymal blood vessels are mainly composed of amyloid beta-peptides. In the present study, either soluble 40-residue amyloid beta-peptide radiolabeled with 125I (I-sAbeta) or [14C]polyethylene glycol ([14C]PEG, a reference material) was briefly infused into one lateral ventricle of normal rats. By 3.5 min, 30% of the I-sAbeta was cleared from ventricular CSF into blood; another 30% was removed over the next 6.5 min. No [14C]PEG was lost from the CSF-brain system during the first 5 min, and only 20% was cleared by 10 min. Much of the I-sAbeta that reached the subarachnoid space was retained by pial arteries and arterioles. Virtually no I-sAbeta was found in brain. The clearance of amyloid beta-peptides from the CSF-brain system, reported herein for normal rats, may be reduced in Alzheimer's disease, thus contributing to amyloid deposition in cerebral tissue and blood vessels
— id: 9392, year: 1996, vol: 67, page: 880, stat: Journal Article,

Prion protein amyloidosis
Ghetti B; Piccardo P; Frangione B; Bugiani O; Giaccone G; Young K; Prelli F; Farlow MR; Dlouhy SR; Tagliavini F
1996 Apr;6(2):127-145, Brain pathology
The prion protein (PrP) plays an essential role in the pathogenesis of a group of sporadic, genetically determined and infectious fatal degenerative diseases, referred to as 'prion diseases', affecting the central nervous system of humans and other mammals. The cellular PrP is encoded by a single copy gene, highly conserved across mammalian species. In prion diseases, PrP undergoes conformational changes involving a shift from alpha-helix to beta-sheet structure. This conversion is important for PrP amyloidogenesis, which occurs to the highest degree in the genetically determined Gerstmann-Straussler-Scheinker disease (GSS) and prion protein cerebral amyloid angiopathy (PrP-CAA), while it is less frequently seen in other prion diseases. GSS and PrP-CAA are associated with point mutations of the prion protein gene (PRNP); these conditions show a broad spectrum of clinical presentation, the main signs being ataxia, spastic paraparesis, extrapyramidal signs and dementia. In GSS, parenchymal amyloid may be associated with spongiform changes or neurofibrillary lesions; in PrP-CAA, vascular amyloid is associated with neurofibrillary lesions. A major component of the amyloid fibrils in the two diseases is a 7 kDa peptide, spanning residues 81-150 of PrP
— id: 9510, year: 1996, vol: 6, page: 127, stat: Journal Article,

Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP
Ghetti B; Piccardo P; Spillantini MG; Ichimiya Y; Porro M; Perini F; Kitamoto T; Tateishi J; Seiler C; Frangione B; Bugiani O; Giaccone G; Prelli F; Goedert M; Dlouhy SR; Tagliavini F
1996 Jan 23;93(2):744-748, Proceedings of the National Academy of Sciences of the United States of America
Deposition of PrP amyloid in cerebral vessels in conjunction with neurofibrillary lesions is the neuropathologic hallmark of the dementia associated with a stop mutation at codon 145 of PRNP, the gene encoding the prion protein (PrP). In this disorder, the vascular amyloid in tissue sections and the approximately 7.5-kDa fragment extracted from amyloid are labeled by antibodies to epitopes located in the PrP sequence including amino acids 90-147. Amyloid-laden vessels are also labeled by antibodies against the C terminus, suggesting that PrP from the normal allele is involved in the pathologic process. Abundant neurofibrillary lesions are present in the cerebral gray matter. They are composed of paired helical filaments, are labeled with antibodies that recognize multiple phosphorylation sites in tau protein, and are similar to those observed in Alzheimer disease. A PrP cerebral amyloid angiopathy has not been reported in diseases caused by PRNP mutations or in human transmissible spongiform encephalopathies; we propose to name this phenotype PrP cerebral amyloid angiopathy (PrP-CAA)
— id: 9512, year: 1996, vol: 93, page: 744, stat: Journal Article,

Prion protein hereditary amyloidosis: Parenchymal and vascular
Ghetti, B; Piccardo, P; Frangione, B; Bugiani, O; Giaccone, G; Young, K; Prelli, F; Farlow, MR; Dlouhy, SR; Tagliavini, F
1996 JUN ;7(3):189-200, Seminars in virology
Prion protein (PrP) amyloidosis is a feature of Gerstmann-Straussler-Scheinker disease (GSS) and prion protein cerebral amyloid angiopathy (PrP-CAA). GSS and PrP-CAA are associated with point mutations of the prion protein gene (PRNP); there is a broad spectrum of clinical presentations and the main signs are ataxia, spastic paraparesis, extrapyramidal signs and dementia. In GSS, parenchymal amyloid may be associated with spongiform changes or neurofibrillary lesions; in PrP-CAA, vascular amyloid is associated with neurofibrillary lesions. In the two diseases, a major component of the amyloid fibrils is a 7 kDa peptide, approximately spanning residues 81-150 of PrP
— id: 52879, year: 1996, vol: 7, page: 189, stat: Journal Article,

beta PP and Tau interaction. A possible link between amyloid and neurofibrillary tangles in Alzheimer's disease
Giaccone G; Pedrotti B; Migheli A; Verga L; Perez J; Racagni G; Smith MA; Perry G; De Gioia L; Selvaggini C; Salmona M; Ghiso J; Frangione B; Islam K; Bugiani O; Tagliavini F
1996 Jan;148(1):79-87, American journal of pathology
Extracellular deposition of amyloid fibrils and intraneuronal accumulation of paired helical filaments (PHFs) are the neuropathological hallmarks of Alzheimer's disease. The major constituent of amyloid fibrils is a 39- to 43-residue peptide (termed A beta), which is derived from a 695- to 770-amino-acid precursor protein (termed beta PP). The main component of PHFs identified so far is the microtubule-associated protein tau. Yet, there is no direct evidence of interconnection between these two pathological states. We report here that antibodies to an epitope located between residues 713 and 723 of beta PP770 (ie, the transmembrane region of beta PP distal to A beta) consistently labeled PHFs in the brain of Alzheimer patients. Solid phase immunoassay showed that a peptide homologous to residues 713 to 730 of beta PP770 bound tau proteins. This beta PP peptide spontaneously formed fibrils in vitro and, in the presence of tau, generated dense fibrillary assemblies containing both molecules. These data suggest that beta PP or beta PP fragments containing the tau binding site are involved in the pathogenesis of PHFs in Alzheimer's disease
— id: 9397, year: 1996, vol: 148, page: 79, stat: Journal Article,

The "nonamyloidogenic" p3 fragment (amyloid beta17-42) is a major constituent of Down's syndrome cerebellar preamyloid
Lalowski M; Golabek A; Lemere CA; Selkoe DJ; Wisniewski HM; Beavis RC; Frangione B; Wisniewski T
1996 Dec 27;271(52):33623-33631, Journal of biological chemistry
Down's syndrome (DS) patients show accelerated Alzheimer's disease (AD) neuropathology, which consists of preamyloid lesions followed by the development of neuritic plaques and neurofibrillary tangles. The major constituents of preamyloid and neuritic plaques are amyloid beta (Abeta) peptides. Preamyloid lesions are defined as being Abeta immunoreactive lesions, which unlike neuritic plaque amyloid are Congo red-negative and largely nonfibrillar ultrastructurally. DS patients can develop extensive preamyloid deposits in the cerebellum, without neuritic plaques; hence, DS cerebellums are a source of relatively pure preamyloid. We biochemically characterized the composition of DS preamyloid and compared it to amyloid in the neuritic plaques and leptomeninges in the same patients. We found that Abeta17-42 or p3 is a major Abeta peptide of DS cerebellar preamyloid. This 26-residue peptide is also present in low quantities in neuritic plaques. We suggest that preamyloid can now be defined biochemically as lesions in which a major Abeta peptide is p3
— id: 9507, year: 1996, vol: 271, page: 33623, stat: Journal Article,

Amyloid beta peptides in cerebellar preamyloid and cortical neuritic plaques of Down's syndrome patients
Lalowski, M.; Golabek, A.; Lemere, C. A.; Selkoe, D. J.; Kolodny, E.; Frangione, B.; Wisniewski, T.
1996 ;22(1-3):1208-145, Abstracts (Society for Neuroscience)
— id: 97641, year: 1996, vol: 22, page: 1208, stat: Journal Article,

Apolipoprotein J and Alzheimer's amyloid beta solubility
Matsubara E; Soto C; Governale S; Frangione B; Ghiso J
1996 Jun 1;316 ( Pt 2):671-679, Biochemical journal
Apolipoprotein J (apoJ) has been found associated with soluble amyloid beta (sA beta) in plasma and cerebrospinal fluid in normal individuals and co-deposited with fibrillar A beta in Alzheimer's cerebrovascular and parenchymal lesions. Although studies in vitro and in vivo indicate that apoJ is a major carrier protein for sA beta, its role in the fibrillogenesis process is not known. We report herein that apoJ in its native high-density lipoprotein lipidic environment is fully active to interact with A beta peptides. Furthermore, apoJ prevents aggregation and polymerization of synthetic A beta in vitro. The interaction was stable for at least 14 days at 37 degrees C in physiologic buffers, and the peptide retrieved after complex dissociation at low pH retained its inherent aggregation properties. In addition, the binding to apoJ protects synthetic A beta from proteolytic degradation; both A beta 1-42 and A beta 1-40 were more resistant to proteolysis by trypsin and chymotrypsin when complexed to apoJ. The data suggest that the interaction may preclude sA beta aggregation in biological fluids and point to a protecting role of apoJ for complexed A beta species
— id: 57410, year: 1996, vol: 316 ( Pt 2), page: 671, stat: Journal Article,

Alzheimer's soluble amyloid beta is a normal component of urine
Matsubara, E.; Governale, S.; Calero, M.; Wisniewski, T.; Frangione, B.; Ghiso, J.
1996 ;22(1-3):1170-33631, Abstracts (Society for Neuroscience)
— id: 97642, year: 1996, vol: 22, page: 1170, stat: Journal Article,

Cerebrovascular amyloidosis in squirrel monkeys and rhesus monkeys: apolipoprotein E genotype
Morelli L; Wei L; Amorim A; McDermid J; Abee CR; Frangione B; Walker LC; Levy E
1996 Jan 29;379(2):132-134, FEBS letters
Some neuropathological changes characteristic of aging and Alzheimer's disease (AD) in humans are present also in senescent non-human primates. The human apoE4 allele is associated with an increased risk of developing late-onset familial and sporadic AD. We found that rhesus monkeys and three subspecies of squirrel monkeys are homozygous for apoE phenotype with arginine at positions 112 and 158 as in human apoE4. However, in both species threonine replaces arginine at position 61 of human apoE. It was previously shown that arginine 61 was critical in determining apoE4 lipoprotein distribution in humans
— id: 56834, year: 1996, vol: 379, page: 132, stat: Journal Article,

Transthyretin gene in Alzheimer's disease patients
Palha JA; Moreira P; Wisniewski T; Frangione B; Saraiva MJ
1996 Feb 9;204(3):212-214, Neuroscience letters
Amyloid beta (Abeta) is known to be the main component of Alzheimer's disease (AD) senile plaques. A homologous peptide is a normal component of biological fluids and is called soluble Abeta (sAbeta). Synthetic peptides homologous to Abeta form amyloid-like fibrils in vitro. This fibril formation can be inhibited by normal human cerebrospinal fluid (CSF) [Wisniewski et al., Ann. Neurol. 34 (1993)]. Furthermore, it has been proposed that normal transthyretin (TTR), which is a component of CSF, can itself bind sAbeta, preventing amyloid fibril formation, and that variants of TTR could be associated with AD [Schwarzman et al., Proc. Natl. Acad. Sci. USA, 91 (1994)]. Because of this possible association, we screened for TTR mutations from 47 sporadic and 19 early-onset familial AD patients using single strand conformation polymorphism analysis. Our results show no correlation between TTR variants and Alzheimer's disease in this group of patients
— id: 9511, year: 1996, vol: 204, page: 212, stat: Journal Article,

Apolipoprotein E, TTR and Alzheimer's disease - General discussion .3
Pepys; Frangione; Goldgaber; Kelly; Arvinte; Masters; Benson; Saraiva; Sipe; Costa
1996 OCT ;199(5):165-169, CIBA Foundation symposium
— id: 52801, year: 1996, vol: 199, page: 165, stat: Journal Article,

Prion protein released by platelets
Perini F; Frangione B; Prelli F
1996 Jun 8;347(9015):1635-1636, Lancet
— id: 57320, year: 1996, vol: 347, page: 1635, stat: Journal Article,

PrP27-30 is a normal soluble prion protein fragment released by human platelets
Perini F; Vidal R; Ghetti B; Tagliavini F; Frangione B; Prelli F
1996 Jun 25;223(3):572-577, Biochemical & biophysical research communications
Prion diseases are neurodegenerative disorders characterized by the accumulation of abnormal isoforms of prion protein (PrPSc) in the central nervous system. PrPSc isoforms differ from their normal homologue (PrPC), in that they possess increased beta-sheet conformation, are partially protease resistant and may be associated with amyloid deposition. Amyloid proteins are thought to derive from soluble precursors or fragments thereof, present in biological fluids, which in the disease state undergo conformational change leading to aggregation and deposition in target tissues. We report here that platelets carry PrP mRNA and release PrPC, a sialoglycoprotein bound to the cell surface by a glycosylphosphatidylinositol (GPI) anchor. Soluble PrPC, and a N-terminal truncated PrPC isoform starting at position 90 are secreted by resting and agonist-stimulated platelets and are detectable after partial deglycosylation of releasates. N-terminal sequence analysis of the soluble 27-30 kDa isoform, GQGGGTHSQ(W)NKP, revealed homology to scrapie PrP27-30, the protease resistant core derived from PrPSc. These findings indicate that in addition to PrPC, platelets process a soluble PrP27-30 isoform. Whether this isoform can be converted in scrapie PrP27-30 remains to be determined
— id: 7031, year: 1996, vol: 223, page: 572, stat: Journal Article,

Proteinase-K-resistant prion protein isoforms in Gerstmann-Straussler-Scheinker disease (Indiana kindred)
Piccardo P; Seiler C; Dlouhy SR; Young K; Farlow MR; Prelli F; Frangione B; Bugiani O; Tagliavini F; Ghetti B
1996 Nov;55(11):1157-1163, Journal of neuropathology & experimental neurology
Gerstmann-Straussler-Scheinker (GSS) disease is a cerebral prion protein (PrP) amyloidosis associated with mutations in the PrP gene (PRNP). A GSS disease variant with mutation at codon 198 (F198S) has been studied in a large Indiana kindred. Biochemical investigations showed that the amyloid protein consists of 11 and 7 kDa fragments of PrP. Immunohistochemical studies showed that in addition to amyloid, these patients accumulate PrP deposits which are neither fluorescent nor birefringent when stained with thioflavin S and Congo red. In the present paper, we analyzed proteinase-K (PK)-resistant PrP in 7 patients with GSS F198S disease. Immunoblots of PK-treated brain extracts show prominent bands of ca. 27-29, 18-19, and 8 kDa. Immunohistochemistry and thioflavin-S-fluorescence show that the amyloid deposits are conspicuous in the cerebellum but sparse in the caudate nucleus. However, immunoblot analysis reveals PK-resistant PrP bands of similar intensity in both regions. Treatment with PK and PNGase F generates a pattern similar to that of PK alone. Our findings suggest that brain extracts from GSS F198S disease contain 3 prominent nonglycosylated PK-resistant PrP fragments forming a pattern not previously described in other prion diseases, which may in part explain the pathology of this GSS disease variant
— id: 9509, year: 1996, vol: 55, page: 1157, stat: Journal Article,

Proteinase K (PK) resistant prion protein (PrP) isoforms in Gerstmann-Straussler-Scheinker disease (GSS) F198S
Piccardo, P; Seiler, C; Dlouhy, S; Young, K; Farlow, M; Prelli, F; Frangione, B; Bugiani, O; Tagliavini, F; Ghetti, B
1996 MAY ;55(5):125-125, Journal of neuropathology & experimental neurology
— id: 52925, year: 1996, vol: 55, page: 125, stat: Journal Article,

Fibrillary glomerulonephritis related to serum fibrillar immunoglobulin-fibronectin complexes
Rostagno A; Vidal R; Kumar A; Chuba J; Niederman G; Gold L; Frangione B; Ghiso J; Gallo G
1996 Nov;28(5):676-684, American journal of kidney diseases
Fibrillary glomerulonephritis is a disease of uncertain origin and pathogenesis characterized by nonamyloidotic fibrils in glomeruli. We report immunohistological, immunochemical, and biochemical studies of a serum fibrillar cryoprecipitate obtained from a patient with fibrillary glomerulonephritis, that formed on prolonged storage at 4 degrees C. By Western blot and amino acid sequence analysis, the cryoprecipitated fibril components consisted of immunoglobulins, heavy chains gamma and mu, light chains kappa and lambda, and fibronectin, similar to the proteins identified by immunofluorescence and immunoelectron microscopy in the glomerular fibrils. These findings support the hypothesis that serum precursors may be the source of the fibrillar deposits and suggest a role for immunoglobulin-fibronectin complexes in the pathogenesis of fibrillary glomerulonephritis
— id: 7254, year: 1996, vol: 28, page: 676, stat: Journal Article,

Biochemical analysis of the interaction of fibronectin with IgG and localization of the respective binding sites
Rostagno A; Williams M; Frangione B; Gold LI
1996 Apr;33(6):561-572, Molecular immunology
Fibronectin (Fn), a mosaic protein composed of multiple copies of three different module types (Fl, F2 and F3), has been found associated with circulating immune complexes (ICs) and immunoglobulin (Ig) aggregates in a variety of IC diseases and myeloproliferative disorders. We have previously shown that a proteolytic fragment of Mr = 25,900 Da, from the NH2-terminal domain of Fn, composed of five type 1 modules (1Fl -5Fl) binds to the major Ig classes under physiologic conditions, suggesting that the presence of Fn in ICs and cryoglobulins results from a physicochemical binding interaction between these two molecules. Using an ELISA, we now show that the interaction between Fn and IgG is: (1) not influenced by any other constituent of plasma; (2) unaffected by temperature; and (3) has an estimated Kd of 3.77 x 10(-9) M. In addition, we have further delineated the respective sites involved in the interaction between Fn and IgG. Recombinant type l module pairs (1Fl.2Fl and 4Fl.5Fl) from the NH2-terminus of Fn, expressed in yeast, were employed in an ELISA and affinity chromatography and compared with the 25.9 kDa (1Fl - 5Fl) fragment and intact Fn for binding to IgG. The 4Fl.5Fl and the 25.9 kDa fragment bound to immobilized IgG and inhibited Fn binding to IgG to nearly the same extent as the intact molecule (IC50: Fn = 6.77 x 1O(-9) M; 25.9 kDa fragment = 5 x 10(-9) M; 4Fl.5Fl = 7.6 x 10(-9) M). Thus, the binding site for IgG on the Fn molecule is localized to and completely conferred by the 4Fl.5Fl module pair (residues 151-244). Similar experiments using papain-generated Fab and Fc fragments of IgG localized the Fn binding site on IgG to the Fe region of the IgG molecule. Fn bound to the Fc fragment with a nearly identical Kd of 3.69 x 10(-9) M, as to intact IgG (3.77 x 10(-9) M). These studies support the hypothesis that the interaction between Fn and Ig may contribute to the pathophysiology of immune complex related disorders
— id: 7043, year: 1996, vol: 33, page: 561, stat: Journal Article,

Inhibition of Alzheimer's amyloidosis by peptides that prevent beta-sheet conformation
Soto C; Kindy MS; Baumann M; Frangione B
1996 Sep 24;226(3):672-680, Biochemical & biophysical research communications
Amyloid beta-peptide (A beta) is a major fibrillar component of neuritic plaques in Alzheimer's disease (AD) brains and is related to the pathogenesis of the disease. We hypothesized that amyloid formation could be inhibited by peptides homologous to A beta (position 17-21) with a similar degree of hydrophobicity, but with a very low propensity to adopt a beta-sheet conformation by incorporating proline residues (anti-beta-sheet peptides or beta-sheet inhibitors). An 11-residue peptide with these characteristics binds to A beta, inhibits A beta fibril formation and partially disaggregates preformed fibrils in vitro. Shorter anti-beta-sheet peptides and analogs containing D-amino acids are also able to inhibit A beta fibrillogenesis. The latter are more resistant to proteolytic degradation and may serve as a starting point to design more efficient peptides derivatives to inhibit amyloidogenesis in vivo
— id: 7092, year: 1996, vol: 226, page: 672, stat: Journal Article,

Meningocerebrovascular amyloidosis associated with a novel transthyretin mis-sense mutation at codon 18 (TTRD 18G) [see comments]
Vidal R; Garzuly F; Budka H; Lalowski M; Linke RP; Brittig F; Frangione B; Wisniewski T
1996 Feb;148(2):361-366, American journal of pathology
We describe a novel transthyretin mutation at codon 18 where Asp is replaced by Gly (D18G) in a Hungarian kindred. This mutation is associated with meningocerebrovascular amyloidosis, producing dementia, ataxia, and spasticity. Fifty different transthyretin mutations are related to amyloid deposition, typically producing a peripheral neuropathy or cardiac dysfunction. These symptoms are absent in this family. Up to now, amyloid-beta (A beta), cystatin C, and prion proteins have been known to be deposited as amyloid in the brain, leading to stroke or dementia. With this report we establish that transthyretin amyloid deposition can also produce central nervous system dysfunction as the major clinical symptom
— id: 6970, year: 1996, vol: 148, page: 361, stat: Journal Article,

Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes. Identification of a novel splice variant
Vidal R; Ghiso J; Wisniewski T; Frangione B
1996 Sep 9;393(1):19-23, FEBS letters
The presenilin 1 (PS1) gene located on chromosome 14 has been linked with the majority of early-onset FAD. The normal biological role of PS1 as well as the mechanism by which mutations in PS1 cause FAD remains unknown. PS1 expression in platelets and the Dami megakaryocytic cell line was examined by Western blot analysis and RT-PCR. Using an anti-N-terminus PS1 antibody we detected PS1 immunoreactive bands of 44, 32 and 27 kDa in both cell types. After RT-PCR we observed that platelets and megakaryocytes carry at least four different PS1 transcripts. One of them is a novel PS1 splice variant that lacks the coding sequence for exon 10 resulting in a shorter 409 amino acid protein
— id: 7919, year: 1996, vol: 393, page: 19, stat: Journal Article,

Apolipoprotein E, Amyloidosis and Alzheimer's disease
Wisniewski T; Frangione B
1996 ;10:171-183, Dementia (Osaka, Japan)
— id: 97675, year: 1996, vol: 10, page: 171, stat: Journal Article,

Molecular biology of brain aging and neurodegenerative disorders
Wisniewski T; Frangione B
1996 ;56(1):267-279, Acta neurobiologiae experimentalis
A significant component of the aging process is genetically determined. Numerous theories of aging exist, many of which postulate the existence of 'longevity genes.' Recent advances in molecular biological and other techniques have allowed a significantly greater understanding of aging and age-related disease. This will be illustrated by four genetic and sporadic diseases: Alzheimer's disease (AD) and related disorders, transthyretin dementia, cerebral amyloid angiopathy-Icelandic type and scrapie related diseases. Alzheimer's disease (AD), the most common of this group, is the leading cause of dementia in Western countries. Recent genetic and biochemical studies have shown the involvement of at least four genes in the pathogenesis of AD. In early-onset familial AD mutations in the beta PP, S182 (presenilin 1) and STM2 (presenilin 2 or E5-1) genes have been found, while in the more common late-onset AD the presence of the apolipoprotein E4 isotype is a major risk factor. Genetic studies have also helped to elucidate the etiology of rarer cerebral amyloidoses such as the recently described Hungarian amyloidosis that is characterized by meningocerebrovascular amyloid deposition, with resultant dementia. This disease is linked to a mutation in the transthyretin gene. It is hoped that in the near future this increase in knowledge will allow the development of therapeutic approaches to slow the aging process
— id: 9513, year: 1996, vol: 56, page: 267, stat: Journal Article,

HB-GAM is a cytokine present in Alzheimer's and Down's syndrome lesions
Wisniewski T; Lalowski M; Baumann M; Rauvala H; Raulo E; Nolo R; Frangione B
1996 Jan 31;7(2):667-671, Neuroreport
The distribution of heparin binding growth associated molecule (HB-GAM) in the cerebral amyloidoses of Alzheimer's disease (AD) and Down's syndrome (DS), conditions characterized by the deposition of amyloid beta (A beta), was investigated immunohistochemically. Antibodies to HB-GAM, a cytokine which plays an important role in brain development and maturation, showed strong immunoreactivity with senile plaques in both AD and DS. Anti-HB-GAM reacted with pre-amyloid lesions, but only when markers of dystrophic neurites were present. The presence of HB-GAM in AD brains, but not in control brains, was confirmed by Western blotting. We suggest that the presence of HB-GAM in A beta lesions is a marker of neuronal injury
— id: 6974, year: 1996, vol: 7, page: 667, stat: Journal Article,

Amyloid beta 1-42 deposits do not lead to Alzheimer's neuritic plaques in aged dogs
Wisniewski T; Lalowski M; Bobik M; Russell M; Strosznajder J; Frangione B
1996 Jan 15;313 ( Pt 2):575-580, Biochemical journal
In alzheimer's disease, amyloid beta (A beta) is deposited in senile plaques and amyloid angiopathy. Longer A beta peptides, which extend to residue 42 (A beta 42), have been suggested to be critical for the seeding of amyloid. Aged dogs develop cerebral vessel amyloid and parenchymal preamyloid lesions. Preamyloid in humans is related to senile plaques, whereas in dogs such progression is rare. We evaluated the composition of aged canine vessel amyloid and preamyloid both biochemically and immunohistochemically. The vessel amyloid extended mainly to residue 40 (A beta 40), while preamyloid contained a mixture of A beta 17-42 and A beta 42, with minimal A beta 40. Our results suggest other factors besides A beta 42 are important for neuritic plaque formation
— id: 6975, year: 1996, vol: 313 ( Pt 2), page: 575, stat: Journal Article,

Presenilin fragments in cerebro-spinal fluid and brain tissue
Wisniewski, T.; Dowjat, W.; Golabek, A.; Miller, D.; Frangione, B.
1996 ;22(1-3):727-671, Abstracts (Society for Neuroscience)
— id: 97643, year: 1996, vol: 22, page: 727, stat: Journal Article,

Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers
Zlokovic BV; Martel CL; Matsubara E; McComb JG; Zheng G; McCluskey RT; Frangione B; Ghiso J
1996 Apr 30;93(9):4229-4234, Proceedings of the National Academy of Sciences of the United States of America
A soluble form of Alzheimer disease amyloid beta-protein (sA beta) is transported in the blood and cerebrospinal fluid mainly complexed with apolipoprotein J (apoJ). Using a well-characterized in situ perfused guinea pig brain model, we recently obtained preliminary evidence that apoJ facilitates transport of sA beta (1-40)-apoJ complexes across the blood-brain barrier and the blood-cerebrospinal fluid barrier, but the mechanisms remain poorly understood. In the present study, we examined the transport process in greater detail and investigated the possible role of glycoprotein 330 (gp330)/megalin, a receptor for multiple ligands, including apoJ. High-affinity transport systems with a Km of 0.2 and 0.5 nM were demonstrated for apoJ at the blood-brain barrier and the choroid epithelium in vivo, suggesting a specific receptor-mediated mechanism. The sA beta (1-40)-apoJ complex shared the same transport mechanism and exhibited 2.4- to 10.2-fold higher affinity than apoJ itself. Binding to microvessels, transport into brain parenchyma, and choroidal uptake of both apoJ and sA beta (1-40)-apoJ complexes were markedly inhibited (74-99%) in the presence of a monoclonal antibody to gp330/megalin and were virtually abolished by perfusion with the receptor-associated protein, which blocks binding of all known ligands to gp330. Western blot analysis of cerebral microvessels with the monoclonal antibody to gp330 revealed a protein with a mass identical to that in extracts of kidney membranes enriched with gp330/megalin, but in much lower concentration. The findings suggest that gp330/megalin mediates cellular uptake and transport of apoJ and sA beta (1-40)-apoJ complex at the cerebral vascular endothelium and choroid epithelium
— id: 9394, year: 1996, vol: 93, page: 4229, stat: Journal Article,

Diffuse senile plaques: amorphous or fibrous?
Bugiani O; Tagliavini F; Giaccone G; Verga L; el-Hachimi K; Foncin JF; Frangione B
1995 Mar;146(3):777-779, American journal of pathology
— id: 9517, year: 1995, vol: 146, page: 777, stat: Journal Article,

Non-Alzheimer's disease amyloidoses of the nervous system
Castano EM; Frangione B
1995 Aug;8(4):279-285, Current opinion in neurology
Amyloidosis and prionosis are disorders of protein conformation. The general mechanisms involved in amyloidogenesis are reviewed here. Recent progress in the molecular pathogenesis of cerebral amyloids is illustrated by three genetic disorders: hereditary amyloid angiopathies of Icelandic and Dutch origins and Gerstmann-Straussler-Scheinker disease
— id: 9515, year: 1995, vol: 8, page: 279, stat: Journal Article,

Apolipoprotein E carboxyl-terminal fragments are complexed to amyloids A and L. Implications for amyloidogenesis and Alzheimer's disease
Castano EM; Prelli F; Pras M; Frangione B
1995 Jul 21;270(29):17610-17615, Journal of biological chemistry
Apolipoprotein E (ApoE) immunoreactivity is consistently present in the senile plaques and neurofibrillary tangles of Alzheimer's disease (AD) brain. In vitro, apoE, and in particular its apoE4 isoform, can bind to and promote fibrillogenesis of the amyloid A beta peptide, the main constituent of senile plaques. These findings, together with the strong genetic association between late onset AD and the E4 allele of apoE, have strengthened the hypothesis that apoE may have a central role in the pathogenesis of AD by modulating A beta cerebral accumulation. However, apoE immunoreactivity is present in all cerebral and systemic amyloidoses tested, and tryptic apoE fragments have been identified in association with amyloid A (AA). In order to further elucidate the interaction between apoE and amyloids, we purified AA and amyloid L (AL) fibrils from patients with familial Mediterranean fever and primary amyloidosis, respectively, and studied the association of apoE with AA and AL proteins. In each case, apoE fragments, detected by Western blot, co-purified with the amyloid fibrils. Microsequencing analysis identified COOH-terminal fragments of apoE, similar to the 10-kDa fragment produced by thrombin digestion that contains the purported binding region to A beta. In vitro co-incubation of AA with purified human apoE resulted in the formation of an SDS-resistant AA.apoE complex and a higher degree of polymerization of the AA peptide. These findings and similar results obtained from AD senile plaques suggest that 1) the carboxyl-terminal fragment of apoE is complexed to amyloid fibrils and resists proteolysis in vivo and 2) apoE may promote amyloidogenesis through a conformation-dependent interaction regardless of the primary structure of the amyloid precursors
— id: 6811, year: 1995, vol: 270, page: 17610, stat: Journal Article,

Fibrillogenesis in Alzheimer's disease of amyloid beta peptides and apolipoprotein E
Castano EM; Prelli F; Wisniewski T; Golabek A; Kumar RA; Soto C; Frangione B
1995 Mar 1;306 ( Pt 2):599-604, Biochemical journal
A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone produces few amyloid-like fibrils. However, apoE produced only a minimal effect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's disease. When recombinant apoE isoforms were used, apoE4 was more efficient than apoE3 at enhancing amyloid formation. These in vitro observations support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease
— id: 8000, year: 1995, vol: 306 ( Pt 2), page: 599, stat: Journal Article,

Apolipoprotein E and amyloidogenesis
Castano EM; Prelli FC; Frangione B
1995 Oct;73(4):457-460, Laboratory investigation
— id: 9514, year: 1995, vol: 73, page: 457, stat: Journal Article,

Amyloids, genes and chaperones
Frangione B; Wisniewski T; Castano E; Ghiso J
Research advances in Alzheimer's disease and related disorders New York : Wiley, 1995,
— id: 4974, year: 1995, vol: , page: 563, stat: Chapter,

THE AMINO-TERMINAL FRAGMENT OF THE AMYLOID BETA-PEPTIDE MODULATES AMYLOID FORMATION
FRANGIONE, B; INESTROSA, NC; CASTANO, EM; SOTOJARA, C
1995 APR 2 ;54(3):87-87, Journal of cellular biochemistry
— id: 87309, year: 1995, vol: 54, page: 87, stat: Journal Article,

Gerstmann-Straussler-Scheinker disease and the Indiana kindred
Ghetti B; Dlouhy SR; Giaccone G; Bugiani O; Frangione B; Farlow MR; Tagliavini F
1995 Jan;5(1):61-75, Brain pathology
Gerstmann-Straussler-Scheinker disease is an autosomal dominant disorder with a wide spectrum of clinical presentations including ataxia, spastic paraparesis, extrapyramidal signs, and dementia. The patients present with symptoms in the third to sixth decade of life and the mean duration of illness is five years. Mutations at codons 102, 105, 117, 145, 198 and 217 of the open reading frame of the prion protein gene have been associated with GSS disease. As a result of the mutations, a substitution at the corresponding residues of the prion protein occurs, or as in the case of the STOP mutation at codon 145, a truncated protein is produced. Neuropathologically, the common denominator is a cerebral prion protein amyloidosis; however, there is significant variability in the pattern of amyloid deposition in regions of the central nervous system among reported families. Amyloidosis coexists with severe spongiform degeneration in patients with the mutation at codon 102, and with neurofibrillary degeneration in the patients with mutation at codons 145, 198 and 217. The development of a transmissible spongiform encephalopathy in animals inoculated with brain tissue from affected subjects with mutation at codon 102 suggests that in some forms of genetically-determined Gerstmann-Straussler-Scheinker disease, and particularly those characterized by severe spongiosis, amyloidogenesis and production of an infectious 'agent' occur concomitantly via mechanisms that are only partially understood
— id: 9520, year: 1995, vol: 5, page: 61, stat: Journal Article,

PRION PROTEIN AMYLOID ANGIOPATHY AND ALZHEIMER NEUROFIBRILLARY TANGLES IN PRNP STOP CODON-145
GHETTI, B; PICCARDO, P; ICHIMIYA, Y; GOEDERT, M; KITAMOTO, T; TATEISHI, J; SPILLANTINI, MG; FRANGIONE, B; BUGIANI, O; GIACCONE, G; PRELLI, F; DLOUHY, SR; TAGLIAVINI, F
1995 MAY ;54(3):415-415, Journal of neuropathology & experimental neurology
— id: 87303, year: 1995, vol: 54, page: 415, stat: Journal Article,

Familial cerebral amyloid angiopathy (British type) with nonneuritic amyloid plaque formation may be due to a novel amyloid protein
Ghiso J; Plant GT; Revesz T; Wisniewski T; Frangione B
1995 Mar;129(1):74-75, Journal of the neurological sciences
— id: 7904, year: 1995, vol: 129, page: 74, stat: Journal Article,

Amyloidosis
Ghiso, Jorge; Vidal, Ruben; Gallo, Gloria; Fragione, Blas
1995 ;35(2):93-102, Revista brasileira de reumatologia
Amiloidose e um termo generico que descreve amplo espectro de doencas caracterizadas pela deposicao de proteinas fibrilares insoluveis em diversos orgaos. As fibrilas depositadas compoem-se predominantemente de proteinas de baixo peso molecular que sao normalmente soluveis sob condicoes fisiologicas. Todos os tipos de amiloide compartilham propriedades fisicas, estruturais e tintoriais comuns: conformacao em placa beta, alto grau de insolubilidade e aparencia fibrilar a microscopia eletronica...
— id: 90048, year: 1995, vol: 35, page: 93, stat: Journal Article,

Amyloid A beta-1-42 does not lead to senile plaques in the canine aging model of Alzheimer's disease
Lalowski, M.; Strosznajder, J.; Russel, M.; Bobik, M.; Frangione, B.; Wisniewski, T.
1995 ;55(SUPPL.):42-75, Acta neurobiologiae experimentalis
— id: 97644, year: 1995, vol: 55, page: 42, stat: Journal Article,

AMYLOID A-BETA-1-42 DOES NOT LEAD TO ALZHEIMERS LESIONS IN AGED DOGS
LALOWSKI, M; GOLABEK, A; BOBIK, M; RUSSELL, M; FRANGIONE, B; WISNIEWSKI, T
1995 ;54(3):432-432, Journal of neuropathology & experimental neurology
— id: 97645, year: 1995, vol: 54, page: 432, stat: Journal Article,

beta-Amyloid precursor protein gene in squirrel monkeys with cerebral amyloid angiopathy
Levy E; Amorim A; Frangione B; Walker LC
1995 Sep-Oct;16(5):805-808, Neurobiology of aging
Senescent nonhuman primates frequently develop cerebral beta-amyloidosis; for reasons that are not yet understood, the primary histological locus of beta-amyloid deposition varies in different species. In aged rhesus monkeys (Macaca mulatta), fibrillar (congophilic) beta-amyloid (A beta) occurs most frequently in senile plaques, whereas in aged squirrel monkeys (Saimiri sciureus) the cerebral blood vessels are most affected. To determine if cerebral beta-amyloid angiopathy (CAA) in squirrel monkeys is related to a species-specific amino acid change in A beta, as was shown in two hereditary human forms of CAA, the beta-amyloid precursor protein (beta PP) cDNA was sequenced. The predicted amino acid sequence of A beta in squirrel monkeys is identical to that in normal humans. Overall, beta PP751 in the squirrel monkey differs from the human sequence only by four amino acids near the N-terminus and in the KPI domain. These findings suggest that other factors most likely predispose aged squirrel monkeys to cerebral amyloid angiopathy. We propose the squirrel monkey as a useful model for studying the factors contributing to human CAA, and for testing diagnostic and therapeutic approaches to this disorder
— id: 6840, year: 1995, vol: 16, page: 805, stat: Journal Article,

Early onset Alzheimer's disease in a South American pedigree from Argentina
Mangone CA; Castano EM; Levy E; Abiusi G; Wisniewski T; Marques MR; Faccio E; Gorelick PB; Frangione B; Sica RE
1995 Jan;91(1):6-13, Acta neurologica Scandinavica
We report the clinical, SPET, immunohistochemical and DNA features of an early-onset familial Alzheimer's disease (FAD) in an Argentine pedigree of South American indian ethnic background. Pedigree spans 5 generations comprising more than 110 biological relatives. Clinical data supported the diagnosis of early onset FAD (mean age at onset 38.9 years) in 10 family members, including 3 with pathological confirmation (mean age at death 48.5). The pattern of transmission suggested autosomal dominant inheritance. Prominent features were mood changes, early language impairment, myoclonus, seizures and cerebellar signs. SPET displayed bilateral frontal, temporo-parietal and cerebellar hypoperfusion in early stages and in an asymptomatic member at risk, suggesting that SPET may have predictive value in this family. Immunohistochemistry showed beta amyloid deposits within neuritic plaques and vessel walls and no anti-PrP immunoreactivity. DNA analysis showed no abnormalities in the beta amyloid precursor protein gene. The identification of additional genetic defects in well characterized independent FAD pedigrees will contribute to the understanding of the pathogenesis of Alzheimer's disease
— id: 9521, year: 1995, vol: 91, page: 6, stat: Journal Article,

Characterization of apolipoprotein J-Alzheimer's A beta interaction
Matsubara E; Frangione B; Ghiso J
1995 Mar 31;270(13):7563-7567, Journal of biological chemistry
The main component of Alzheimer's amyloid deposits, A beta, has been found also as a soluble (sA beta) normal constituent of biological fluids and cell culture supernatants. Whether or not sA beta is the immediate precursor of A beta, it is clear that peptides with the same amino acid sequence can have both fibrillar and non-fibrillar conformations. The interconversion mechanism from one form to another is presently under intensive investigation. We have previously described that (i) a synthetic peptide A beta 1-40 immobilized on affinity matrices was able to retrieve apolipoprotein J (apoJ) from plasma and cerebrospinal fluid; and (ii) the interaction of sA beta with apoJ occurs in vivo, as demonstrated by the ability of anti-apoJ to co-precipitate sA beta from normal cerebrospinal fluid. We have characterized the binding between A beta 1-40 and apoJ and found that the interaction is saturable, specific, and reversible. The dissociation constant of 2 x 10(-9) M is indicative of high affinity binding. The stoichiometry of the reaction is 1:1; apoJ has five times more affinity for fresh A beta 1-40 than for the aggregated peptide. Competitive inhibition studies carried out with apolipoprotein E (isoforms E2, E3, and E4), transthyretin, vitronectin, and alpha 1-antichymotrypsin indicate that the complex apoJ.A beta 1-40 cannot be dissociated by any of these competitors at physiologic concentrations. The data strongly suggest that apoJ plays an important role as a carrier protein for sA beta
— id: 8065, year: 1995, vol: 270, page: 7563, stat: Journal Article,

COLLOID INCLUSIONS OF PARKINSONS-DISEASE - FURTHER IMMUNOHISTOCHEMICAL CHARACTERIZATION WITH SPECIAL REFERENCE TO LEWY BODIES
OGBURN, J; SAMBAMURTI, K; WISNIEWSKI, T; FRANGIONE, B; DUDLEY, A; PAPPOLLA, M
1995 MAY ;54(3):445-445, Journal of neuropathology & experimental neurology
— id: 87308, year: 1995, vol: 54, page: 445, stat: Journal Article,

Tau protein directly interacts with the amyloid beta-protein precursor: implications for Alzheimer's disease
Smith MA; Siedlak SL; Richey PL; Mulvihill P; Ghiso J; Frangione B; Tagliavini F; Giaccone G; Bugiani O; Praprotnik D; et al
1995 Apr;1(4):365-369, Nature medicine
The simultaneous presence of intracellular neurofibrillary tangles (NFT) and extracellular senile plaques in Alzheimer's disease (AD) suggests that the two lesions could be synergistically interrelated. However, although the main protein components of NFT and senile plaques, tau (tau) and amyloid beta-protein, respectively, are well characterized, the molecular mechanisms responsible for their deposition in lesions are unknown. We demonstrate, using four independent techniques, that tau directly interacts with a conformation-dependent domain of the amyloid beta-protein precursor (beta PP) encompassing residues beta PP714-723. The putative tau-binding domain includes beta PP717 mutation sites that are associated with familial forms of AD. Our findings strongly suggest that NFT and senile plaques, often thought of as independent structures, may play a role in each other's formation during the pathogenesis of AD
— id: 9398, year: 1995, vol: 1, page: 365, stat: Journal Article,

The alpha-helical to beta-strand transition in the amino-terminal fragment of the amyloid beta-peptide modulates amyloid formation
Soto C; Castano EM; Frangione B; Inestrosa NC
1995 Feb 17;270(7):3063-3067, Journal of biological chemistry
Amyloid-beta peptide (A beta) consists of a hydrophobic C-terminal domain (residues 29-42) that adopts beta-strand conformation and an N-terminal domain (amino acids 10-24) whose sequence permits the existence of a dynamic equilibrium between an alpha-helix and a beta-strand. In this paper we analyzed the effect of the alternate N-terminal conformations on amyloid fibril formation through the study of the analogous A beta peptides containing single amino acidic substitutions. The single mutation of valine 18 to alanine induces a significant increment of the alpha-helical content of A beta, determined by Fourier transform infrared spectroscopy and circular dichroism and dramatically diminishes fibrillogenesis, measured by turbidity, thioflavine T binding, Congo red staining, and electron microscopic examination. In hereditary Dutch cerebral hemorrhage with amyloidosis (a variant of Alzheimer's disease), the substitution of glutamine for glutamic acid at position 22 decreased the propensity of the A beta N-terminal domain to adopt an alpha-helical structure, with a concomitant increase in amyloid formation. We propose that A beta exists in an equilibrium between two species: one 'able' and another 'unable' to form amyloid, depending on the secondary structure adopted by the N-terminal domain. Thus, manipulation of the A beta secondary structure with therapeutical compounds that promote the alpha-helical conformation may provides a tool to control the amyloid deposition observed in Alzheimer's disease patients
— id: 9518, year: 1995, vol: 270, page: 3063, stat: Journal Article,

Fibrillogenesis of synthetic amyloid-beta peptides is dependent on their initial secondary structure
Soto C; Castano EM; Kumar RA; Beavis RC; Frangione B
1995 Nov 17;200(2):105-108, Neuroscience letters
Synthetic peptides containing the sequence of Alzheimer's amyloid-beta peptide (A beta) spontaneously form amyloid-like fibrils in vitro, and have been extensively used to study the factors that modulate fibrillogenesis. Contradictory observations have been reported regarding the neurotoxicity of A beta and the influence of some A beta-binding proteins on in vitro A beta amyloid formation. In this study, we show that A beta 1-40 synthetic peptides obtained from different suppliers, have significantly distinct fibrillogenic properties. No differences were detected in the chemical structure or in the initial assembly state by mass spectroscopy, reverse-phase high performance liquid chromatography and denaturing or non-denaturing gel electrophoresis. However, there was a direct correlation between the ability of soluble peptides to form amyloid and their percentage of beta-sheet structure, as determined by electron microscopy, fluorescence associated to thioflavine T bound to amyloid, and circular dichroism. The data suggest that the determinant factor of A beta fibrillogenesis is the secondary structure adopted by the peptide in its soluble state
— id: 6965, year: 1995, vol: 200, page: 105, stat: Journal Article,

Two conformational states of amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease
Soto C; Frangione B
1995 Feb 17;186(2-3):115-118, Neuroscience letters
Since the discovery of soluble amyloid-beta (sA beta), it became clear that the same amino acid sequence can have both a fibrillar or a soluble state. In this work, we describe the isolation of two different species derived from synthetic A beta(1-40) differing in their conformational and fibrillogenesis properties. The separation was performed taking advantage of the fact that only one species is sedimentable by centrifugation after 2 weeks of incubation at 1 mg/ml. One species is highly amyloidogenic (A beta ac) and has an antiparallel beta-sheet structure and the other one is poorly amyloidogenic (A beta nac) and contains mainly random coil or alpha-helix structure. Chemical changes were not detected in the primary structure of both species and the differences in the physical properties and very likely in biological behaviour are thought to have a conformational basis. We propose that the transformation of the non-amyloidogenic into the amyloidogenic conformation could be the fundamental event in the pathological polymerization of sA beta and in the development of Alzheimer's disease
— id: 6753, year: 1995, vol: 186, page: 115, stat: Journal Article,

Hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D): clinicopathological studies
Wattendorff AR; Frangione B; Luyendijk W; Bots GT
1995 Jun;58(6):699-705, Journal of neurology neurosurgery & psychiatry
Clinical and neuropathological findings are reported in 63 patients with hereditary cerebral haemorrhage with amyloid angiopathy. Patients had mostly recurrent strokes, and at least 80% of these were haemorrhages. Almost a third of the patients died within a year of their first and only recorded haemorrhage, half of them within two weeks. This angiopathy was restricted to the cerebral and cerebellar cortex and its covering leptomeninges. As the most important consequence, haemorrhagic infarcts and haemorrhages occurred in the subcortical white matter--that is, the region most vulnerable to impaired cortical circulation. Further development of these subcortical lesions gives rise to the fatal haemorrhages seen at necropsy. In so far as dementia occurs this is likely to result from multiple microinfarcts or haemorrhages. In most cases preamyloid lesions or diffuse plaques and early plaques were seen. No other type of plaque or neurofibrillary degeneration was found. The plaques occur in conjunction with the angiopathy, but may not occur even when the angiopathy is severe. In one patient plaques were totally absent. Angiopathy and plaques may be the result of the same mutation, the expression of which is governed by tissue factors or phenotypic differences between individual subjects
— id: 9516, year: 1995, vol: 58, page: 699, stat: Journal Article,

Amyloidosis in Alzheimer's disease
Wisniewski T; Frangione B
1995 Aug 12;346(8972):441-441, Lancet
— id: 7908, year: 1995, vol: 346, page: 441, stat: Journal Article,

Conformational mimicry in Alzheimer's disease. Role of apolipoproteins in amyloidogenesis
Wisniewski T; Golabek AA; Kida E; Wisniewski KE; Frangione B
1995 Aug;147(2):238-244, American journal of pathology
Several apolipoproteins are known to be closely associated with amyloid fibrillogenesis. Serum amyloid A, apolipoprotein (apo) AII and apo A1 are each deposited as biochemically distinct forms of amyloid. Late-onset Alzheimer's disease is linked to one isotype of apo E, apo E4. Apo E and apo E4 in particular have been shown to modulate amyloid fibril formation by amyloid-beta peptides in vitro. Furthermore, the carboxy terminus of apo E has been shown to be a constituent of plaque amyloid. We show immunohistochemically and electron microscopically the presence of apo A1 in senile plaques. The intact apo A1 can itself form amyloid-like fibrils in vitro that are Congo Red positive. We propose that some proteins when misfolded can propagate this misfolding to identical units, either autocatalytically or to other proteins that are induced to fold into the same abnormal conformation. This conformational mimicry may initiate and/or augment fibrillogenesis in Alzheimer's disease
— id: 6878, year: 1995, vol: 147, page: 238, stat: Journal Article,

Is Alzheimer's disease an apolipoprotein E amyloidosis?
Wisniewski T; Lalowski M; Golabek A; Vogel T; Frangione B
1995 Apr 15;345(8955):956-958, Lancet
The presence of the apolipoprotein E4 allele has been identified as a major risk factor for late-onset Alzheimer's disease. Apolipoprotein E has also been found immunohistochemically in Alzheimer's disease lesions. We biochemically isolated amyloid beta from senile plaques and found that a carboxyl-terminal fragment (residues 216-299) of apolipoprotein E co-purified. In vitro this fragment from recombinant apolipoprotein E could form amyloid-like fibrils, which were Congo-red positive. Thus senile plaques may contain both amyloid beta and apolipoprotein E amyloid fibrils
— id: 6779, year: 1995, vol: 345, page: 956, stat: Journal Article,

The influence of apolipoprotein E isotypes on Alzheimer's disease pathology in 40 cases of Down's syndrome
Wisniewski T; Morelli L; Wegiel J; Levy E; Wisniewski HM; Frangione B
1995 Jan;37(1):136-138, Annals of neurology
— id: 9519, year: 1995, vol: 37, page: 136, stat: Journal Article,

S182 protein in Alzheimer's disease neuritic plaques
Wisniewski T; Palha JA; Ghiso J; Frangione B
1995 Nov 18;346(8986):1366-1366, Lancet
— id: 7909, year: 1995, vol: 346, page: 1366, stat: Journal Article,

APOLIPOPROTEIN-E AMYLOID IN ALZHEIMERS PLAQUE
WISNIEWSKI, T; GOLABEK, A; LALOWSKI, M; VOGEL, T; FRANGIONE, B
1995 ;54(3):411-411, Journal of neuropathology & experimental neurology
— id: 97647, year: 1995, vol: 54, page: 411, stat: Journal Article,

APOLIPOPROTEIN-E IN ALZHEIMERS-DISEASE
WISNIEWSKI, T; GOLABEK, A; LALOWSKI, M; VOGEL, T; FRANGIONE, B
1995 ;38(2):324-324, Annals of neurology
— id: 97646, year: 1995, vol: 38, page: 324, stat: Journal Article,

The blood brain barrier regulates transport of Alzheimer's amyloid ? and apolipoproteins E and J
Zlokovic B; Mackic J; Martel C; Wisniewski T; Frangione B; Ghiso J
Research advances in Alzheimer's disease and related disorders New York : Wiley, 1995,
— id: 4975, year: 1995, vol: , page: 585, stat: Chapter,

CHARACTERIZATION BY RADIOSEQUENCING OF THE CARBOXY-TERMINAL DERIVATIVES PRODUCED FROM NORMAL AND MUTANT AMYLOID-BETA PROTEIN PRECURSORS
CHEUNG, TT; GHISO, J; SHOJI, M; CAI, XD; GOLDE, T; GANDY, S; FRANGIONE, B; YOUNKIN, S
1994 JUL ;15(7):S54-S54, Neurobiology of aging
— id: 52404, year: 1994, vol: 15, page: S54, stat: Journal Article,

CHARACTERIZATION BY RADIOSEQUENCING OF THE CARBOXYL-TERMINAL DERIVATIVES PRODUCED FROM NORMAL AND MUTANT AMYLOID-BETA PROTEIN PRECURSORS
CHEUNG, TT; GHISO, J; SHOJI, M; CAI, XD; GOLDE, T; GANDY, S; FRANGIONE, B; YOUNKIN, S
1994 MAR ;1(1):30-38, Amyloid
The 39-43 amino acid (similar to 4 kD) amyloid beta-protein (A beta) deposited as amyloid Alzheimer's disease is an infernal peptide beginning 99 residues from the COOH end of a much larger amyloid beta-protein precursor (beta APP). In cultured cells, normal processing of the beta APP produces similar to 8.7, similar to 9.6, similar to 10.9, and similar to 11.4 kD COOH-terminal derivatives that appear to contain all or part of the A beta domain. In this study, we metabolically labeled transfected human neuroblastoma (M17) cells with [H-3]phenylalanine plus [S-35]methionine and then radiosequenced the immunoprecipitated COOH-terminal beta APP derivatives faking advantage of the fact that the A beta has phenylalanines at positions 4, 19, and 20, and a single methionine at position 35. Our analysis of the derivatives produced by transfected M17 cells expressing beta APP(695) confirms that the similar to 8.7 kD COOH-terminal derivative begins at A beta(17) and indicates that the similar to 9.6 and similar to 10.9 kD derivatives begin at A beta(10) and A beta(4) respectively. Significantly we find that the 11.4 kD derivative begins at A beta(1). Thus normal beta APP processing produces a potentially amyloidogenic COOH-terminal derivative that has the AP domain intact at its amino terminus. We have previously shown that cells expressing beta APP(Delta NL) a mutant linked to familial Alzheimer's disease, produce an increased amount of the 11.4 kD COOH-terminal derivative and secrete more A beta. Radiosequencing of these derivatives showed that the Delta NL mutant is cleaved at the same location as wild type beta APP producing an 11.4 kD COOH-terminal derivative and A beta that both begin at A beta(1). Thus the Delta NL mutation appears to accelerate a cleavage that releases an 11.4 kD COOH-terminal derivative identical to that normally produced from wild type beta APP, and it appears that this 11.4 kD derivative is further processed to release excess A beta
— id: 87453, year: 1994, vol: 1, page: 30, stat: Journal Article,

Chaperoning Alzheimer's amyloids
Frangione B; Wisniewski T; Ghiso J
1994 ;15 Suppl 2:S97-S99, Neurobiology of aging
— id: 6619, year: 1994, vol: 15 Suppl 2, page: S97, stat: Journal Article,

AMYLOIDS, GENES AND CHAPERONES IN ALZHEIMERS-DISEASE
FRANGIONE, B
1994 JUL ;15(7):S39-S39, Neurobiology of aging
— id: 52403, year: 1994, vol: 15, page: S39, stat: Journal Article,

Potential role of apolipoprotein-E in fibrillogenesis
Gallo G; Wisniewski T; Choi-Miura NH; Ghiso J; Frangione B
1994 Sep;145(3):526-530, American journal of pathology
Immunohistochemical and biochemical studies have demonstrated several different proteins in amyloid deposits that are not intrinsic components of the fibril itself but may play a role in their deposition and fibril formation. We compared the distribution of several amyloid-associated proteins, ie, amyloid P component, apolipoprotein-E, apolipoprotein-J, and vitronectin, in the deposits of several different amyloids, in particular light chain amyloid, with those in the deposits of nonamyloid monoclonal immunoglobulin, which may be considered a form of preamyloid disease. Although 100% of amyloid specimens (7 amyloid A, 15 immunoglobulin light chain, and 1 transthyretin) had amyloid P component and 100% had apolipoprotein-E (2 amyloid A, 10 immunoglobulin light chain, and 1 transthyretin) co-localized with the primary amyloid protein, none of the monoclonal nonamyloid cases (14 light chain deposition disease and 6 light and heavy chain deposition disease) had amyloid P component and only 1 of 11 had apolipoprotein-E. On the other hand, staining for apolipoprotein-J and vitronectin was positive in 100% of cases of amyloid and nonamyloid monoclonal deposits. The association between the presence of apolipoprotein-E and amyloid P component in the fibrillar form of monoclonal light chain deposits and their absence in the nonfibrillar form of deposits suggest a role for these proteins in the process of fibrillogenesis. This lends support for the previously proposed concept that apolipoprotein-E functions as a pathological chaperone by altering the conformation of amyloidogenic proteins
— id: 9401, year: 1994, vol: 145, page: 526, stat: Journal Article,

APP processing, A beta-amyloidogenesis, and the pathogenesis of Alzheimer's disease
Gandy S; Caporaso G; Buxbaum J; Frangione B; Greengard P
1994 Mar-Apr;15(2):253-256, Neurobiology of aging
— id: 9524, year: 1994, vol: 15, page: 253, stat: Journal Article,

Familial Gerstmann-Straussler-Scheinker disease with neurofibrillary tangles
Ghetti B; Tagliavini F; Giaccone G; Bugiani O; Frangione B; Farlow MR; Dlouhy SR
1994 Feb;8(1):41-48, Molecular neurobiology
Patients affected with Gerstmann-Straussler-Scheinker disease from two families, one from Indiana and one of Swedish origin, have been studied. The patients are clinically characterized by cerebellar ataxia, extrapyramidal signs, and dementia. Accumulation of amyloid deposits and neurofibrillary tangles are the most conspicuous neuropathologic features. In the patients from the Indiana family, the amyloid contains an 11-kDa peptide, an amyloidogenic degradation product of the prion protein. The neurofibrillary tangles are composed of paired helical filaments and immunoreact with antibody to A68, an abnormally phosphorylated form of the microtubule-associated protein tau. In these families, the disease is caused by a point mutation in the PRNP gene. In the Indiana family, the mutation is at codon 198, and in the Swedish family at codon 217
— id: 9526, year: 1994, vol: 8, page: 41, stat: Journal Article,

Characterization of a novel processing pathway for Alzheimer's amyloid beta precursor protein
Ghiso J; Gardella JE; Liem L; Gorevic PD; Frangione B
1994 Apr 25;171(1-2):213-216, Neuroscience letters
Amyloid beta (A beta) is a normal proteolytic fragment of a large precursor protein (beta PP) which undergoes altered conformation, leading to fibril formation. Two main beta PP processing pathways have been described, and we are now reporting the characterization of a third beta PP pathway. A membrane-associated 16 kDa component identified in human platelets isolated from normal donors. Based on size, immunoreactivity and amino acid sequence analysis, the fragment is a C-terminal beta PP component which starts at position 642 (APP770 numbering) and contains the intact A beta sequence. The presence of this novel pathway of beta PP processing in resting platelets suggest that it occurs as a normal event
— id: 9402, year: 1994, vol: 171, page: 213, stat: Journal Article,

Unifying features of systemic and cerebral amyloidosis
Ghiso J; Wisniewski T; Frangione B
1994 Feb;8(1):49-64, Molecular neurobiology
Amyloidosis is a generic term for a group of clinically and biochemically diverse diseases that are characterized by the deposition of an insoluble fibrillar protein in the extracellular space. Over 16 biochemically distinct amyloids are known. Despite this diversity, all amyloids have a particular ultrastructural and tinctorial appearance, a beta-pleated sheet structure, and are codeposited with a group of amyloid-associated proteins. The most common amyloidosis is Alzheimer's disease (AD), where A beta is the main component of the amyloid. Recently it has been found that A beta exists as a normal soluble protein (sA beta) in biological fluids. This links AD more closely to some of the systemic amyloidoses, where the amyloid precursor is found in the circulation normally. Numerous mutations have been found in the A beta precursor (beta PP) gene, associated with familial AD. Many mutations are also found in some of the hereditary systemic amyloidoses. For example, over 40 mutations in the transthyretin (TTR) gene are associated with amyloid. However, both A beta and TTR related amyloid deposition can occur with no mutation. The pathogenesis of amyloid is complex, and appears to be associated with genetic and environmental risk factors that can be similar in the systemic and cerebral amyloidoses
— id: 9403, year: 1994, vol: 8, page: 49, stat: Journal Article,

Binding of soluble beta-amyloid in vitro and in vivo
Golabek, A.; Marques, M.; Koji, I.; Ghiso, J.; Herbert, J.; Frangione, B.; Wisniewski, T.
1994 ;20(1-2):1643-64, Abstracts (Society for Neuroscience)
— id: 97648, year: 1994, vol: 20, page: 1643, stat: Journal Article,

Ocular amyloid deposition in familial amyloidosis, Finnish: an analysis of native and variant gelsolin in Meretoja's syndrome
Kivela T; Tarkkanen A; Frangione B; Ghiso J; Haltia M
1994 Sep;35(10):3759-3769, Investigative ophthalmology & visual science. IOVS
PURPOSE: To analyze the deposition of amyloid and its precursors in eyes of patients with familial amyloidosis, Finnish (FAF; Meretoja's syndrome), a hereditary systemic amyloidosis. METHODS. Autopsy eyes from three patients with FAF and ten control eyes were studied by Congo red staining and with antibodies to the nonmutated part of gelsolin (GS-2C4), the mutated gelsolin Asn-187 fragment (AGel), and amyloid-P component (AP). RESULTS. Congo red and antisera to AP and AGel bound to amyloid deposits in the cornea and conjunctiva, the sclera, the perineurium of ciliary nerves, the walls of ciliary vessels, the optic nerve sheaths, the stroma of the ciliary body, and along the choriocapillaris. mAb GS-2C4 bound weakly and focally to most deposits and strongly around the choriocapillaris. It labeled the corneal epithelium and endothelium, keratocytes, scleral fibroblasts, trabecular and lens epithelial cells, the ciliary muscle and epithelium, the iris sphincter and dilator, and stromal cells of the conjunctiva and uveal tract. CONCLUSIONS. Local production, especially in the cornea, conjunctiva, sclera, and ciliary muscle, and systemic deposition, particularly in blood vessles and in the sclera, may contribute to amyloid deposits in FAF. To explain the complex pattern of deposition, microenvironmental factors such as lamellar architecture of the cornea and sclera, altered processing of gelsolin, or blood-tissue barriers must be invoked. In addition to corneal lattice dystrophy type II, the observed deposits help to explain glaucoma in patients with FAF
— id: 9400, year: 1994, vol: 35, page: 3759, stat: Journal Article,

The soluble form of Alzheimer's amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma
Koudinov A; Matsubara E; Frangione B; Ghiso J
1994 Dec 15;205(2):1164-1171, Biochemical & biophysical research communications
The amyloid fibrils of Alzheimer's neuritic plaques and cerebral blood vessels are mainly composed of aggregated forms of a 39 to 44 amino acids peptide, named amyloid beta (A beta). A similar although soluble form of A beta (sA beta) has been identified in plasma, cerebrospinal fluid and cell culture supernatants, indicating that it is produced under physiologic conditions. We report here that sA beta in normal human plasma is associated with lipoprotein particles, in particular to the HDL3 and VHDL fractions where it is complexed to ApoJ and, to a lesser extent, to ApoAI. This was assessed by immunoprecipitation experiments of purified plasma lipoproteins and lipoprotein-depleted plasma and confirmed by means of amino acid sequence analysis. Moreover, biotinylated synthetic peptide A beta 1-40 was traced in normal human plasma in in vitro experiments. As in the case of sA beta, biotinylated A beta 1-40 was specifically recovered in the HDL3 and VHDL fractions. This data together with the previous demonstration that A beta 1-40 is taken up into the brain via a specific mechanism and possibly as an A beta 1-40-ApoJ complex indicate a role for HDL3- and VHDL-containing ApoJ in the transport of the peptide in circulation and suggest their involvement in the delivery of sA beta across the blood-brain barrier
— id: 6664, year: 1994, vol: 205, page: 1164, stat: Journal Article,

BETA-PROTEIN PRECURSOR INTERACTION WITH TAU
PERRY, G; SIEDLAK, S; MULVIHILL, P; RICHEY, PL; PRAPROTNIK, D; GHISO, J; FRANGIONE, B; KALARIA, R; SMITH, MA
1994 JUL ;15(7):S78-S78, Neurobiology of aging
— id: 52406, year: 1994, vol: 15, page: S78, stat: Journal Article,

Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3
Sanan DA; Weisgraber KH; Russell SJ; Mahley RW; Huang D; Saunders A; Schmechel D; Wisniewski T; Frangione B; Roses AD; et al
1994 Aug;94(2):860-869, Journal of clinical investigation
Late-onset and sporadic Alzheimer's disease are associated with the apolipoprotein E (apoE) type 4 allele expressing the protein isoform apoE4. Apolipoprotein E binds avidly to beta amyloid (A beta) peptide, a major component of senile plaque of Alzheimer's disease, in an isoform-specific manner. The apoE4 isoform binds to A beta peptide more rapidly than apoE3. We observed that soluble SDS-stable complexes of apoE3 or apoE4, formed by coincubation with A beta peptide, precipitated after several days of incubation at 37 degrees C with apoE4 complexes precipitating more rapidly than apoE3 complexes. A beta(1-28) and A beta(1-40) peptides were incubated in the presence or absence of apoE3, apoE4, or bovine serum albumin for 4 d at 37 degrees C (pH 7.3). Negative stain electron microscopy revealed that the A beta peptide alone self-assembled into twisted ribbons containing two or three strands but occasionally into multistranded sheets. The apoE/A beta coincubates yielded monofibrils 7 nm in diameter. ApoE4/A beta coincubates yielded a denser matrix of monofibrils than apoE3/A beta coincubates. Unlike purely monofibrillar apoE4/A beta coincubates, apoE3/A beta coincubates also contained double- and triple-stranded structures. Both apoE isoforms were shown by immunogold labeling to be uniformly distributed along the A beta peptide monofibrils. Monofibrils appeared earlier in apoE4/A beta than in apoE3/A beta in time-course experiments. Thus apoE3 and apoE4 each interact with beta amyloid peptide to form novel monofibrillar structures, apoE4 more avidly, a finding consistent with the biochemical and genetic association between apoE4 and Alzheimer's disease
— id: 9523, year: 1994, vol: 94, page: 860, stat: Journal Article,

Amyloid fibrils in Gerstmann-Straussler-Scheinker disease (Indiana and Swedish kindreds) express only PrP peptides encoded by the mutant allele
Tagliavini F; Prelli F; Porro M; Rossi G; Giaccone G; Farlow MR; Dlouhy SR; Ghetti B; Bugiani O; Frangione B
1994 Nov 18;79(4):695-703, Cell
Gerstmann-Straussler-Scheinker (GSS) disease is a cerebral amyloidosis linked to mutations of the PRNP gene. We previously reported that the amyloid protein in the Indiana kindred of GSS is an internal fragment of prion protein (PrP). To investigate whether this fragment originates only from mutant or from both mutant and wild-type PrP, we have characterized amyloid proteins purified from patients of the Indiana and Swedish GSS families. These patients were heterozygous for the Met-Val polymorphism at PRNP codon 129 and carried a mutation at PRNP codon 198 (Phe-->Ser) and codon 217 (Gln-->Arg), respectively. The smallest amyloid subunit was a 7 kDa peptide spanning residues approximately 81 to approximately 150 in the Indiana patient and approximately 81 to approximately 146 in the Swedish patient. In both patients, only Val was present at position 129. Since Val-129 was in coupling phase with Ser-198 and Arg-217, our findings indicate that only the mutant PrP is involved in amyloid formation in both kindreds
— id: 9522, year: 1994, vol: 79, page: 695, stat: Journal Article,

7-KD AMYLOID SUBUNIT IN GSS DISEASE (INDIANA AND SWEDISH KINDREDS) CONTAINS ONLY PRP PE
TAGLIAVINI, F; PRELLI, F; PORRO, M; ROSSI, G; GIACCONE, G; FARLOW, MR; DLOUHY, SR; GHETTI, B; BUGIANI, O; FRANGIONE, B
1994 JUL ;15(7):S143-S143, Neurobiology of aging
— id: 52410, year: 1994, vol: 15, page: S143, stat: Journal Article,

Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro
Wisniewski T; Castano EM; Golabek A; Vogel T; Frangione B
1994 Nov;145(5):1030-1035, American journal of pathology
Numerous studies have established a linkage between the apolipoprotein (apo) E4 allele and late-onset Alzheimer's disease. It remains unclear if apo E plays a direct role in the pathogenesis of Alzheimer's disease and what, if any, are its significant interactions with amyloid beta (A beta) and tau. Apo E has been found immunohistochemically in all types of amyloid deposits and apo E fragments have been isolated from amyloid. Furthermore, apo E has been shown to bind soluble A beta. It has been proposed that apo E acts to promote and/or modulate A beta fibril formation. It is well established that peptides homologous to A beta will form amyloid-like fibrils in solution. With the use of electron microscopy and a thioflavin T assay for fibril formation we found that apo E and apo E4 in particular enhance this spontaneous fibrillogenesis of A beta peptides under the in vitro conditions used. These in vitro data suggest that the apo E4 isoform is a risk factor for Alzheimer's disease that acts to accelerate a process that can occur in its absence
— id: 6777, year: 1994, vol: 145, page: 1030, stat: Journal Article,

Alzheimer's disease and soluble A beta
Wisniewski T; Ghiso J; Frangione B
1994 Mar-Apr;15(2):143-152, Neurobiology of aging
The discovery of soluble amyloid beta (sA beta) suggests that the role of amyloid in Alzheimer's disease (AD) is similar to the previously studied systemic amyloidoses and alters the notion that membrane damage is the initial event in AD. The disease state is characterized by the abnormal accumulation of a normal degradative peptide, which becomes resistant to further proteolysis due to a conformational change. Mutations in the beta PP gene have been found in a very small percentage of AD cases; hence other factors, both genetic and environmental, need to be identified. Priority needs to be given to detailed studies of the structural differences between sA beta and the A beta in amyloid deposits. This will help uncover the determining factors governing the aggregation of sA beta. These structural alterations may be critical for the possible toxic effects A beta and/or associated proteins (molecular chaperones, e.g., apolipoprotein E) have on brain cell function
— id: 6778, year: 1994, vol: 15, page: 143, stat: Journal Article,

The amino acid sequence of neuritic plaque amyloid from a familial Alzheimer's disease patient
Wisniewski T; Lalowski M; Levy E; Marques MR; Frangione B
1994 Feb;35(2):245-246, Annals of neurology
— id: 9525, year: 1994, vol: 35, page: 245, stat: Journal Article,

Brain uptake of circulating apolipoproteins J and E complexed to Alzheimer's amyloid beta
Zlokovic BV; Martel CL; Mackic JB; Matsubara E; Wisniewski T; McComb JG; Frangione B; Ghiso J
1994 Dec 15;205(2):1431-1437, Biochemical & biophysical research communications
Amyloid beta (A beta) is a fibrillar component in Alzheimers' disease amyloid deposits and a soluble peptide (sA beta) normally present in body fluids. We have recently reported that the blood-brain barrier (BBB) has a capability to control cerebrovascular sequestration and transport of circulating sA beta. In this study, we examined whether two circulating amyloid-associated proteins shown to bind sA beta, apolipoproteins J (apo J) and E (apo E), can cross the BBB alone and/or complexed to a synthetic peptide homologous to a major form of sA beta, sA beta 1-40. Brain perfusion experiments in guinea pigs showed significant uptake of both apo J and sA beta 1-40-apo J complexes. In contrast, blood-brain transport of sA beta 1-40-apo E was negligible, while apo E had a limited access across the BBB, indicating that the apo E found within the brain is produced locally. It is concluded that sA beta 1-40 binding to apo J and apo E results in significant (> 100-fold) difference in brain uptake of their respective complexes. We hypothesize that in normal brain apo J facilitates sA beta transport
— id: 9399, year: 1994, vol: 205, page: 1431, stat: Journal Article,

Transport of Alzheimer's amyloid beta and apolipoproteins E and J at the blood-brain barrier
Zlokovic, B. V.; Mackic, J. B.; Martell, C. J.; Wisniewski, T.; Frangione, B.; Ghiso, J.
1994 ;20(1-2):1642-1437, Abstracts (Society for Neuroscience)
— id: 97649, year: 1994, vol: 20, page: 1642, stat: Journal Article,

THE BLOOD-BRAIN-BARRIER REGULATES TRANSPORT OF ALZHEIMERS AMYLOID-BETA AND APOLIPOPROTEIN-E AND APOLIPOPROTEIN-J
ZLOKOVIC, BV; MACKIC, JB; MARTELL, CL; WISNIEWSKI, T; FRANGIONE, B; GHISO, J
1994 JUL ;15(7):S80-S80, Neurobiology of aging
— id: 52407, year: 1994, vol: 15, page: S80, stat: Journal Article,

Beta PP participates in PrP-amyloid plaques of Gerstmann-Straussler-Scheinker disease, Indiana kindred
Bugiani O; Giaccone G; Verga L; Pollo B; Frangione B; Farlow MR; Tagliavini F; Ghetti B
1993 Jan;52(1):64-70, Journal of neuropathology & experimental neurology
Gerstmann-Straussler-Scheinker disease in the Indiana kindred is pathologically characterized by deposits of PrP-amyloid, neurofibrillary tangles and degenerating neurites. The aim of this study was to investigate seven patients of different ages for beta PP and A beta immunoreactivities associated with PrP-amyloid deposits and degenerating neurites. In one asymptomatic individual with PrP-amyloid deposits, Alz50 and A beta immunoreactivities were absent. In six symptomatic patients, the degenerating neurites surrounding PrP-amyloid deposits were labeled by Alz50 and by antibodies to synaptophysin, ubiquitin and the N- and C-terminal domains of beta PP. In one symptomatic, senile patient, A beta immunoreactivity was present in the extracellular space, often in association with PrP-amyloid deposits. The analysis of the immunohistochemical findings suggested that in the Indiana kindred the intracellular accumulation of beta PP, synaptophysin and ubiquitinated material most probably revealed a reaction of neurites to PrP-amyloid, whereas the extracellular deposition of A beta was likely an age-related phenomenon
— id: 9531, year: 1993, vol: 52, page: 64, stat: Journal Article,

Alzheimer's disease and amyloid
Frangione B; Wisniewski T; Ghiso J
Amyloid and amyloidosis 1993 New York : Parthenon, 1993,
— id: 5144, year: 1993, vol: , page: 310, stat: Chapter,

Alzheimer's disease and Dutch variant: Opposing faces of a single coin
Frangione, Blas; Wisniewski, Thomas; Tagliavini, Fabrizio; Bugiani, Orso; Ghiso, Jorge
Alzheimer's disease : advances in clinical and basic research New York : Wiley, 1993,
— id: 4969, year: 1993, vol: , page: 387, stat: Chapter,

Light Chain Deposition disease : biochemical characterization of tissue deposits
Gallo G; Boctor F; Frangione B; Ghiso J
Amyloid and amyloidosis 1993 New York : Parthenon, 1993,
— id: 5145, year: 1993, vol: , page: 280, stat: Chapter,

Characterization and fibrillogenesis of a construct (C109) homologus to the carboxyl end of the amyloid precusor protein of Alzheimer's disease
Gardella JE; Gorgone G; Ghiso J; Castano E; Frangione B; Gorevic PD
Alzheimer's disease : advances in clinical and basic research New York : Wiley, 1993,
— id: 5143, year: 1993, vol: , page: 411, stat: Chapter,

High-level expression and in vitro mutagenesis of a fibrillogenic 109-amino-acid C-terminal fragment of Alzheimer's-disease amyloid precursor protein
Gardella JE; Gorgone GA; Candela L; Ghiso J; Castano EM; Frangione B; Gorevic PD
1993 Sep 15;294(Pt 3):667-674, Biochemical journal
We amplified DNA encoding the 3' 109 codons of Alzheimer's-disease amyloid precursor protein (APP) inclusive of the beta protein (A beta) and cytoplasmic domains from cDNA using oligonucleotide primers designed to facilitate cloning into the T7 expression vector pT7Ad23K13. We also modified this construct to generate recombinant molecules incorporating two recently described APP mutants by site-directed mutagenesis. Both native C109 (deletion construct inclusive of the C-terminal 109 residues of APP) and constructs with a single mutation at codon 642 (T-->G, resulting in a substitution of glycine for valine) or a double mutation at codons 595 (G-->T, substituting asparagine for lysine) and 596 (A-->C, substituting leucine for methionine) were expressed in Escherichia coli to levels of 5-20% of total bacterial protein after induction. The major constituent of expressed C109 protein had an apparent molecular mass of 16-18 kDa by SDS/PAGE and appeared to be the full-length construct by size and N-terminal microsequencing. Also present was a 4-5 kDa species that co-purified with C109, constituting only approximately 1% of expressed protein, which was revealed by Western-blot analysis with antibodies specific for A beta epitopes and after biotinylation of purified recombinant C109. This fragment shared N-terminal sequence with, and appeared to arise by proteolysis of, full-length C109 in biosynthetic labelling experiments. C109 spontaneously precipitated after dialysis against NaCl or water, and with prolonged (> 20 weeks) standing was found by electron microscopy to contain a minor (< 5%) fibrillar component that was reactive with antibodies to a C-terminal epitope of APP. Recombinant C109 appears to duplicate some of the biochemical and physicochemical properties of C-terminal A beta-inclusive fragments of APP that have been found in transfected cells, brain cortex and cerebral microvessels
— id: 9406, year: 1993, vol: 294, page: 667, stat: Journal Article,

The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex
Ghiso J; Matsubara E; Koudinov A; Choi-Miura NH; Tomita M; Wisniewski T; Frangione B
1993 Jul 1;293(Pt 1):27-30, Biochemical journal
The amyloid fibrils deposited in Alzheimer's neuritic plaque cores and cerebral blood vessels are mainly composed of aggregated forms of a unique peptide, 39-42 amino acids long, named amyloid beta (A beta). A similar, although soluble, A beta ('sA beta') has been identified in cerebrospinal fluid, plasma and cell supernatants, indicating that it is normally produced by proteolytic processing of its precursor protein, amyloid precursor protein (APP). Using direct binding experiments we have isolated and characterized an 80 kDa circulating protein that specifically interacts with a synthetic peptide identical with A beta. The protein was unmistakably identified as SP-40,40 or ApoJ, a cytolytic inhibitor and lipid carrier, by means of amino acid sequence and immunoreactivity with specific antibodies. Immunoprecipitation with anti-SP-40,40 retrieved soluble A beta from cerebrospinal fluid, indicating that the interaction occurs in vivo
— id: 8397, year: 1993, vol: 293, page: 27, stat: Journal Article,

Epitope map of two polyclonal antibodies that recognize amyloid lesions in patients with Alzheimer's disease
Ghiso J; Wisniewski T; Vidal R; Rostagno A; Frangione B
1993 ;1:19-20, Parkinson/Alzheimer digest
— id: 101632, year: 1993, vol: 1, page: 19, stat: Journal Article,

The cerebrospinal fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (APO J), an inhibitor of the complement membrane attack complex
Ghiso, Jorge; Matsubara, Etsuro; Koudinov, Alexei; Wisniewski, Thomas; Frangione, Blas
1993 ;19(1-3):19-S80, Abstracts (Society for Neuroscience)
— id: 97650, year: 1993, vol: 19, page: 19, stat: Journal Article,

Synthetic peptides corresponding to different mutated regions of the amyloid gene in familial Creutzfeldt-Jakob disease show enhanced in vitro formation of morphologically different amyloid fibrils
Goldfarb LG; Brown P; Haltia M; Ghiso J; Frangione B; Gajdusek DC
1993 May 15;90(10):4451-4454, Proceedings of the National Academy of Sciences of the United States of America
We synthesized polypeptides corresponding to sequences encoded by normal and mutant alleles in the regions of codon 178 (Asp-->Asn) and codon 200 (Glu-->Lys) of the chromosome 20 amyloid gene that have been linked to familial Creutzfeldt-Jakob disease. Peptide suspensions from both regions spontaneously formed amyloid fibrils with different morphological characteristics and aggregation tendencies. Fibrillar arrays were denser and more profuse in mutant than in normal peptide suspensions and were even more marked when the homologous mutant and normal peptides were mixed together. Preparations from the region of codon 200 were in all cases more fibrillogenic than corresponding peptides from the region of codon 178. These in vitro observations support the hypothesis that amino acid changes from pathogenic single-allele point mutations in Creutzfeldt-Jakob disease may nucleate the in vivo folding behavior of the normal host protein to favor formation of insoluble amyloid fibrils
— id: 9407, year: 1993, vol: 90, page: 4451, stat: Journal Article,

Immunohistochemical analysis of lattice corneal dystrophies types I and II
Kivela T; Tarkkanen A; McLean I; Ghiso J; Frangione B; Haltia M
1993 Dec;77(12):799-804, British journal of ophthalmology
Corneal buttons from four patients with lattice corneal dystrophy (LD) type I, thought to be an isolated corneal amyloidosis, and from six patients with LD type II, part of systemic familial amyloidosis, Finnish type (FAF; Meretoja's syndrome), were studied by immunohistochemistry to determine the differential distribution in the amyloid deposits of amyloid P component (AP), mutated gelsolin specific for FAF, and native gelsolin. In both types of LD, antibodies to AP labelled lattice lines and a discontinuous layer of amyloid deposits under Bowman's layer. In LD type II, particularly, they also reacted with streak-like amyloid deposits between corneal almellae, especially in the limbal region. While the anti-FAF antiserum strongly labelled all amyloid deposits in LD type II, it failed to react unequivocally with them in LD type I. Both in LD type I and in two control specimens representing granular dystrophy, the monoclonal antibody (MAb) GS-2C4 to gelsolin faintly labelled some deposits, while in LD type II it reacted non-homogeneously with most amyloid deposits. In all specimens, MAb GS-2C4 labelled corneal epithelial cells and occasional stromal keratocytes and endothelial cells. The results suggest that Meretoja's syndrome, a systemic disease, can be diagnosed even retrospectively from corneal buttons subjected to histopathological study
— id: 9405, year: 1993, vol: 77, page: 799, stat: Journal Article,

Proteolytic processing of human amyloid beta protein precursor in insect cells. Major carboxyl-terminal fragment is identical to its human counterpart
Ramabhadran TV; Gandy SE; Ghiso J; Czernik AJ; Ferris D; Bhasin R; Goldgaber D; Frangione B; Greengard P
1993 Jan 25;268(3):2009-2012, Journal of biological chemistry
The predominant component of amyloid plaques of Alzheimer's disease is the amyloid beta protein (A beta), a 39-42-amino-acid peptide derived by proteolysis of a family of precursors known as amyloid precursor proteins (APP). In mammalian brain and in cultured mammalian cells, the release of APP amino-terminal fragments into the extracellular medium occurs by a proteolytic cleavage within the A beta domain, thereby precluding amyloidogenesis. Infection of Sf9 insect cells with baculovirus vectors containing APP cDNAs results in high levels of APP expression. The concomitant release of amino-terminal fragments of APP and the production of carboxyl-terminal, cell-associated cleavage products are observed. Here we demonstrate by direct protein microsequencing that the proteolytic processing of APP in the Sf9 cells generates a prominent carboxyl-terminal species that is identical to that produced in human cells, suggesting that the major pathway for proteolytic processing of APP is conserved among metazoans
— id: 9409, year: 1993, vol: 268, page: 2009, stat: Journal Article,

Gelsolin immunoreactivity in corneal amyloid, wound healing, and macular and granular dystrophies
Rodrigues MM; Rajagopalan S; Jones K; Nirankari V; Wisniewski T; Frangione B; Gorevic PD
1993 May 15;115(5):644-652, American journal of ophthalmology
Immunohistologic studies of tissue sections obtained from patients with type 1 or type 2 lattice corneal dystrophy, polymorphic amyloid degeneration, or gelatinous amyloid degeneration were performed by using a monoclonal antibody raised to a chymotryptic fragment inclusive of the carboxy-terminal half of plasma gelsolin, and also with a series of polyclonal antibodies specific for synthetic peptides corresponding to immunogenic epitopes of gelsolin. These epitopes are parts of sequences at the amino- and carboxy-terminal ends of gelsolin, as well as adjacent to and inclusive of the codon 187 mutant 7-11 kD fragment that has been shown to be the subunit protein of amyloid fibrils occurring systemically in patients affected by Finnish type familial amyloidosis. These antibodies were also tested on tissue sections obtained from patients with granular and macular corneal dystrophy, corneal wounds, and normal control corneas. Specificity of staining was established by absorption with gelsolin purified from plasma, or the appropriate synthetic peptide. Gelsolin immunoreactivity was detected in the conjunctival and skin amyloid in familial amyloidosis by using familial amyloid (Finnish type) antibody. In other types of corneal amyloid, including lattice dystrophy type 1, immunoreactivity with gelsolin and synthetic peptides was observed adjacent to the deposits, but rarely within them. In macular dystrophy, variable staining of the deposits could result from the association of subunit proteins with glycosaminoglycans
— id: 9528, year: 1993, vol: 115, page: 644, stat: Journal Article,

Ubiquitinated neurites are associated with preamyloid and cerebral amyloid beta deposits in patients with hereditary cerebral hemorrhage with amyloidosis Dutch type
Tagliavini F; Giaccone G; Bugiani O; Frangione B
1993 ;85(3):267-271, Acta neuropathologica
Hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D) is characterized clinically by recurrent strokes and pathologically by deposition of amyloid beta (A beta) in cerebral vessel walls and, to a lesser extent, in the neuropil. Distinct from Alzheimer's disease, amyloid formation in HCHWA-D is not associated with neurofibrillary changes. Since a central issue in the pathophysiology of Alzheimer's disease and related conditions is the role of A beta in the neurodegenerative process, we investigated HCHWA-D brains for the presence of neuritic abnormalities using antibodies to ubiquitin and to phosphorylated neurofilaments. The study showed that amyloid deposits in the vessel walls and in the neuropil were surrounded by abnormal ubiquitinated neurites, suggesting that A beta deposition induces neuritic changes
— id: 9529, year: 1993, vol: 85, page: 267, stat: Journal Article,

A68 is a component of paired helical filaments of Gerstmann-Straussler-Scheinker disease, Indiana kindred
Tagliavini F; Giaccone G; Prelli F; Verga L; Porro M; Trojanowski JQ; Farlow MR; Frangione B; Ghetti B; Bugiani O
1993 Jul 9;616(1-2):325-329, Brain research
Gerstmann-Straussler-Scheinker disease in the Indiana kindred is pathologically characterized by prion protein amyloid deposits and neurofibrillary tangles (NFT) with paired helical filaments (PHF). Using antibodies to various domains of the tau molecule, we investigated the composition of PHF in this family by immunocytochemistry and immunoblot analysis. The results indicate that A68 is a component of NFT in this family as it is in Alzheimer's disease, and suggest that post-translational modifications of tau leading to formation of A68 are not unique to Alzheimer's disease
— id: 9527, year: 1993, vol: 616, page: 325, stat: Journal Article,

Sequencing of the Alzheimer's APP gene Dutch variant (APP-D)
Vidal RG; Fernandez-Madrid I; Frangione B; Levy E
1993 ;2(6):496-497, Human mutation
— id: 9530, year: 1993, vol: 2, page: 496, stat: Journal Article,

Cerebrospinal fluid inhibits Alzheimer beta-amyloid fibril formation in vitro
Wisniewski T; Castano E; Ghiso J; Frangione B
1993 Oct;34(4):631-633, Annals of neurology
Alzheimer's disease is characterized by the deposition of beta-protein (A beta) as amyloid. Recently, it was found that A beta is a normal component of serum and cerebrospinal fluid. Synthetic peptides homologous to A beta form amyloid-like fibrils spontaneously in water or physiological solutions. Using a peptide homologous to A beta 1-40, we find that fibril formation is inhibited by the presence of cerebrospinal fluid
— id: 6554, year: 1993, vol: 34, page: 631, stat: Journal Article,

Apolipoprotein E: binding to soluble Alzheimer's beta-amyloid
Wisniewski T; Golabek A; Matsubara E; Ghiso J; Frangione B
1993 Apr 30;192(2):359-365, Biochemical & biophysical research communications
Apolipoprotein E (apo E) is associated with Alzheimer's beta-amyloid (A beta) in senile plaques. A beta is now known to be a normal soluble peptide (sA beta) found in the cerebrospinal fluid (CSF) and other biological fluids. We have used synthetic A beta peptides bound to affinity membranes in order to determine whether apo E or any other amyloid associated protein will bind to these membranes, when they are bathed in CSF. Under these conditions apo E, as well as another apolipoprotein, apolipoprotein J (Apo J), bound to the membranes. Using ELISA and ligand binding studies, we found a high avidity binding of A beta peptides to apo E. This suggests that apo E, as well as other related proteins may bind not only amyloid A beta but also sA beta. This interaction may be critical in amyloid formation
— id: 9408, year: 1993, vol: 192, page: 359, stat: Journal Article,

ALZHEIMERS AMYLOID BETA-SUBUNIT IS PRESENT IN PREAMYLOID DEPOSITS AND IN CSF
WISNIEWSKI, T; WEGIEL, J; WISNIEWSKI, HM; FRANGIONE, B
1993 ;43(4):A422-A422, Neurology
— id: 97629, year: 1993, vol: 43, page: A422, stat: Journal Article,

Apolipoprotein E and Alzheimer's beta-amyloid fibril formation
Wisniewski, Thomas; Golabek, Adam; Ghiso, Jorge; Frangione, Blas
1993 ;19(1-3):1034-633, Abstracts (Society for Neuroscience)
— id: 97651, year: 1993, vol: 19, page: 1034, stat: Journal Article,

Blood-brain barrier transport of circulating Alzheimer's amyloid beta
Zlokovic BV; Ghiso J; Mackic JB; McComb JG; Weiss MH; Frangione B
1993 Dec 30;197(3):1034-1040, Biochemical & biophysical research communications
The origin of amyloid beta (A beta) deposited in brain and cerebral blood vessels of patients with Alzheimer's Disease (AD) is not known. In this study, we tested whether soluble A beta (sA beta) can cross the blood-brain barrier (BBB). An in vivo vascular brain perfusion model and capillary depletion technique in guinea-pigs were used to determine cerebral capillary sequestration and blood-brain transport of a synthetic peptide identical with residues 1-40 (SP-40) of A beta. A saturable, specific binding of SP-40 has been demonstrated at the luminal side of the BBB, with the Kd of 25 +/- 2 nM, and Bmax of 188 +/- 11 fmol/min/g of isolated microvessels. A specific transcellular BBB transport of SP-40 into brain parenchyma exhibited the Km of 49 +/- 10 nM, and Vmax of 111 +/- 19 fmol/min/g of capillary depleted brain. We concluded that the BBB has the capability to control the cerebrovascular sequestration and blood-to-brain transport of circulating sA beta. Hence, sA beta can contribute to both cerebrovascular and parenchymal amyloid formation
— id: 9404, year: 1993, vol: 197, page: 1034, stat: Journal Article,

H chain V region sequences of three human monoclonal IgM with anti-myelin-associated glycoprotein activity
Ayadi H; Mihaesco E; Congy N; Roy JP; Gendron MC; Laperriere J; Prelli F; Frangione B; Brouet JC
1992 May 1;148(9):2812-2816, Journal of immunology
The amino acid sequence corresponding to the V region H chain gene used by three monoclonal IgM directed to the myelin-associated glycoprotein (MAG) is presented. They all belonged to the VHIII variability subgroup, but each may well represent a new member of this family inasmuch as their homology with previously sequenced VHIII genes was less than 80%. Strikingly, there was no greater homology between the H chain V regions of the anti-MAG IgM. Partial amino acid sequence data indicated that these V regions were joined to as yet unidentified DH segments; however, two H chains used very similar DH, possibly indicating that this sequence was involved in the fine specificity of the IgM for MAG. All H chains included a JHIV region. These data, together with results obtained from the sequence of the three kappa L chains of the same IgM molecules (Mihaesco, E., H. Ayadi, N. Congy, M. C. Gendron, J. P. Roy, H. Heyermann, B. Frangione, and J. C. Brouet. 1989. J. Biol. Chem. 264:21481), indicate that the repertoire of VL and VH gene segments used by anti-MAG IgM is quite diverse, in contrast to previous structural data obtained for other human monoclonal IgM autoantibodies. Possibly, these differences reflect distinct pathogenesis
— id: 9536, year: 1992, vol: 148, page: 2812, stat: Journal Article,

ACCELERATED INSTRUCTIVE FIBRILLOGENESIS IN THE DUTCH VARIANT OF ALZHEIMER'S DISEASE
FRANGIONE B; WISNIEWSKI T; GHISO J
1992 ;43(16 PART E):200-A422, Journal of cellular biochemistry. Supplement
— id: 97652, year: 1992, vol: 43, page: 200, stat: Journal Article,

ACCELERATED INSTRUCTIVE FIBRILLOGENESIS IN THE DUTCH VARIANT OF ALZHEIMER'S DISEASE AND THE ROLE OF PATHOLOGICAL CHAPERONES IN AMYLOID FORMATION
FRANGIONE B; WISNIEWSKI T; GHISO J
1992 ;13(SUPPL. 1):S73-S80, Neurobiology of aging
— id: 97600, year: 1992, vol: 13, page: S73, stat: Journal Article,

Beta protein precursor expression in human platelets and a megakaryocyte cell line. Possible implications for the origin of cerebral amyloidosis in Alzheimer's disease
Gardella JE; Gorgone GA; Munoz PC; Ghiso J; Frangione B; Gorevic PD
1992 Sep;67(3):303-313, Laboratory investigation
BACKGROUND: The origin of the amyloid beta protein (A beta) that is the main constituent of amyloid fibrils occurring in the senile plaques and cerebrovasculature of individuals afflicted with Alzheimer's Disease, Down's Syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis--Dutch Type, and Sporadic Cerebral Amyloid Angiopathy, is central to the pathogenesis of these disorders. Evidence exists to support a neuronal and/or a vascular origin. We have reported that platelets may serve as one possible source of the A beta sequence via an intact, membrane-associated Beta Protein Precursor (beta PP) which is encoded by a platelet transcript (BBRC 173:1292-1298, 1990). EXPERIMENTAL DESIGN: Immunoaffinity chromatography and western blotting of extracted cellular proteins, polymerase chain reaction amplification of beta PP mRNA, fluorescence activated flow cytometric analysis, and confocal scanning laser microscopy have been employed to characterize the presence and distribution of thrombocytic beta PP. RESULTS: Immunoblot analysis with antibodies specific for the carboxyl-terminal end of beta PP indicates that platelets and the Dami megakaryocyte cell line express membrane-associated species of intact beta PP ranging in molecular weight from 110 to 140 kilodaltons (kd), as well as carboxyl-terminal reactive forms ranging from 16 to 22 kd. Thrombin stimulation of platelets induces the release of five soluble beta PP species, which possess apparent isofocusing points in the range of 4.1-5.5. By contrast, extracts of peripheral blood mononuclear cells enriched by ficoll centrifugation, endothelial cells and a B cell line were not immunoreactive by western blot, even though beta PP transcripts could be amplified by polymerase chain reaction. The distribution of platelet beta PP was localized by flow cytometric analysis and scanning laser microscopy, using fluorescein-labeled antibodies. Study of the subcellular distribution of platelet beta PP indicates that these translation products are accumulated in discrete foci throughout the thrombocyte, possibly corresponding to secretory granules. CONCLUSIONS: The size of the carboxyl-terminal forms of beta PP indicate that the A beta sequence is present as a membrane associated constituent in unstimulated platelets, and may represent alternative pathways of beta PP processing. Cleavage or other abnormal processing of platelet-associated beta PP in Alzheimer's disease provides one mechanism whereby cerebral amyloid might derive from the circulation
— id: 9413, year: 1992, vol: 67, page: 303, stat: Journal Article,

Characterization of Alzheimer amyloid precursor protein transcripts in platelets and megakarocytes
Gardella JE; Gorgone GA; Newman P; Frangione B; Gorevic PD
1992 Apr 27;138(2):229-232, Neuroscience letters
Immunoblot analyses indicate that the platelet is a reservoir of several Alzheimer amyloid precursor protein (APP) isoforms, including C-terminal reactive species which could potentially serve as the precursor of the amyloid beta protein (AB*) in Alzheimer's disease (AD). Since platelets are known to sequester several plasma proteins from the blood, we employed the polymerase chain reaction (PCR) to amplify reverse transcribed mRNA and detect the 3 major APP transcripts (APP695,751,770) in platelets and the Dami megakaryocyte cell line. PCR amplification of glycoprotein IIb and HLA-DR mRNA was used to demonstrate that APP transcripts were derived from cells of megakaryocytic lineage, and the results were compared with those obtained from peripheral blood mononuclear cells, human umbilical vein endothelial cells, B lymphocyte and astrocytoma cell lines. The identity of PCR products was confirmed by hybridization with APP specific oligonucleotide probes, and sequencing of amplified segments
— id: 9537, year: 1992, vol: 138, page: 229, stat: Journal Article,

A 109-amino-acid C-terminal fragment of Alzheimer's-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell adhesion
Ghiso J; Rostagno A; Gardella JE; Liem L; Gorevic PD; Frangione B
1992 Dec 15;288(Pt 3):1053-1059, Biochemical journal
Amyloid beta (A beta), the major constituent of the fibrils composing senile plaques and vascular amyloid deposits in Alzheimer's disease (AD) and related disorders, is a 39-42-residue self-aggregating degradation peptide of a larger multidomain membrane glycoprotein designated amyloid precursor protein (APP). An array of biological functions has been assigned to different APP domains, including growth regulation, neurotoxicity, inhibitory activity of serine proteinases and promotion of cell-cell and cell-matrix interactions. A beta is generated through an as-yet-unknown catabolic pathway that by-passes or inhibits the cleavage of APP within the A beta sequence. We have identified a 16 kDa intermediate APP C-terminal fragment containing A beta in leptomeningeal vessels of aged normal individuals and AD patients by means of its immunoreactivity with a panel of four different anti-(APP C-terminal) antibodies, indicating a different pathway of APP processing. Previous studies have indicated that the APP C-terminal domain is the most likely to be involved in cell-matrix interactions. A 109-amino-acid construct C109 with a sequence analogous to the C-terminal of APP (positions 587-695 of APP695), similar in length and immunoreactivity to the 16 kDa fragment, was found to promote cell adhesion. By use of synthetic peptides, this activity was initially located to the extracellular 28 residues of A beta. Inhibition studies demonstrated that the sequence RHDS (amino acids 5-8 of A beta, corresponding to residues 601-604 of APP695 was responsible for the adhesion-promoting activity. The interaction is dependent on bivalent cations and can be blocked either by the tetrapeptides RHDS and RGDS or by an anti-(beta 1 integrin) antibody. Thus, through integrin-like surface receptors, APP or its derivative proteolytic fragments containing the sequence RHDS may modulate cell-cell or cell-matrix interactions
— id: 9410, year: 1992, vol: 288, page: 1053, stat: Journal Article,

Epitope map of two polyclonal antibodies that recognize amyloid lesions in patients with Alzheimer's disease
Ghiso J; Wisniewski T; Vidal R; Rostagno A; Frangione B
1992 Mar 1;282(Pt 2):517-522, Biochemical journal
Two synthetic peptides with sequences identical with those of fragments of the extracellular domain of the Alzheimer's-disease amyloid precursor protein (APP) were used to raise antibodies. SP28 comprises positions 597-624 of the APP695 isoform, whereas SP41 extends towards the N-terminus (amino acids 584-624) and contains the entire SP28 peptide. Using e.l.i.s.a. and inhibition experiments we identified the two beta-turn-containing segments 602-607 and 617-624 as the epitopes recognized by anti-SP41 and anti-SP28 respectively. Both antibodies immunolabelled amyloid lesions in brains from Alzheimer's-disease patients and patients with related disorders, whereas they were unreactive in control brains. However, when probed on immunoblots, anti-SP28 failed to detect full-length APP from baculovirus-infected Sf9 cells, and anti-SP41 reacted weakly compared with other anti-APP antisera. The data suggest that these antibodies are directed to conformational epitopes not existent in the native molecules but present after alternative APP processing
— id: 9414, year: 1992, vol: 282, page: 517, stat: Journal Article,

Prion protein preamyloid and amyloid deposits in Gerstmann-Straussler-Scheinker disease, Indiana kindred [published erratum appears in Proc Natl Acad Sci U S A 1993 Jan 1;90(1):302]
Giaccone G; Verga L; Bugiani O; Frangione B; Serban D; Prusiner SB; Farlow MR; Ghetti B; Tagliavini F
1992 Oct 1;89(19):9349-9353, Proceedings of the National Academy of Sciences of the United States of America
Gerstmann-Straussler-Scheinker disease (GSS) is a familial neurological disorder pathologically characterized by amyloid deposition in the cerebrum and cerebellum. In GSS, the amyloid is immunoreactive to antisera raised against the prion protein (PrP) 27-30, a proteinase K-resistant peptide of 27-30 kDa that is derived by limited proteolysis from an abnormal isoform of a neuronal sialoglycoprotein of 33-35 kDa designated PrPSc. Polyclonal antibodies raised against synthetic peptides homologous to residues 15-40 (P2), 90-102 (P1), and 220-232 (P3) of the amino acid sequence deduced from hamster PrP cDNA were used to investigate immunohistochemically the distribution of PrP and PrP fragments in the brains of two patients from the Indiana kindred of GSS. Two types of anti-PrP-immunoreactive deposits were found: (i) amyloid deposits, which were exclusively labeled by anti-P1 antiserum to residues 90-102 of PrP, and (ii) preamyloid deposits, which were labeled by all anti-PrP antisera but did not exhibit the tinctorial and optical properties of amyloid. The latter appeared as diffuse immunostaining of the neuropil that targeted to areas in which amyloid deposits were most abundant. They were partially resistant to proteinase K digestion and consisted ultrastructurally of amorphous, flaky, electron-dense material. These findings substantiate our previous observation that the major amyloid component in the GSS Indiana kindred is an internal fragment of PrP and indicate that full-length abnormal isoforms of PrP and/or large PrP fragments accumulate in brain regions most affected by amyloid deposition. These findings support the view that in the GSS Indiana kindred a stepwise degradation of PrP occurs in situ in the process of amyloid fibril formation
— id: 9533, year: 1992, vol: 89, page: 9349, stat: Journal Article,

Localization of the cleavage sites on fibronectin following digestion by urokinase
Gold LI; Rostagno A; Frangione B; Passalaris T
1992 Dec;50(4):441-452, Journal of cellular biochemistry
Urokinase (u-PA) proteolytically cleaves both human plasma (pFn) and cellular (cFn) dimeric fibronectin (M(r) 440,000) into four major polypeptides of approximately M(r) 210,000, 200,000, 25,000, and 6,000. Amino acid sequence analysis of the polypeptide fragments indicated that the enzymatic cleavage of Fn occurs at two sites: 1) between an arginine/alanine peptide bond located C-terminal to residue 259; this cleavage liberates the N-terminal M(r) 25,000 fragment and the M(r) 210,000 and M(r) 200,000 polypeptides derived from the A and B chains of Fn, respectively; and 2) between an arginine/threonine peptide bond located C-terminal to residue 2,299, thereby yielding an M(r) 6,000 dimeric fragment containing the C-terminal interchain disulfide bonds. Predigestion of Fn with u-PA increased the molecule's vulnerability to further attack by the enzymes plasmin and cathepsin D. These data provide further biochemical evidence for the proteolytic cleavage of fibronectin by plasminogen activators and substantiate that u-PA digestion of Fn may be an initial event in the local degradation of the extracellular matrix by malignant cells, possessing elevated levels of these enzymes
— id: 9532, year: 1992, vol: 50, page: 441, stat: Journal Article,

Gelsolin gene mutation--at codon 187--in familial amyloidosis, Finnish: DNA-diagnostic assay
Haltia M; Levy E; Meretoja J; Fernandez-Madrid I; Koivunen O; Frangione B
1992 Feb 1;42(3):357-359, American journal of medical genetics
Familial amyloidosis, Finnish (FAF), is an autosomal dominant form of systemic amyloidosis with lattice corneal dystrophy and progressive cranial neuropathy as principal clinical manifestations. We have shown that the novel amyloid fibril protein found in these patients is an internal degradation fragment of gelsolin, an actin-binding protein, and that it contains an amino acid substitution, asparagine for aspartic acid at position 15, that is due to a guanine-to-adenine transversion corresponding to codon 187 of human plasma gelsolin cDNA. To test that this mutation cosegregates with the disease high-molecular-weight genomic DNA was isolated from autopsied tissues or lymphocytes of 23 patients, 6 healthy relatives and 20 unrelated healthy control persons. Specific fragments were amplified with the polymerase chain reaction for oligonucleotide hybridization analysis using the slot-blot technique. The guanine-to-adenine transversion was found in all FAF patients tested, but in none of the control subjects. Our results show that the mutation (G to A) cosegregates with the disease phenotype, and that the slot-blot analysis can be used as a diagnostic assay, including prenatal evaluation
— id: 9539, year: 1992, vol: 42, page: 357, stat: Journal Article,

The heterogeneity of bovine IgG2--V. Differences in the primary structure of bovine IgG2 allotypes
Heyermann H; Butler JE; Frangione B
1992 Sep;29(9):1147-1152, Molecular immunology
The partial amino acid sequences of the gamma chains of the bovine IgG2a(A1) and IgG2a(A2) allotypes were determined. Sequence differences were found in the CH1 domain, the hinge region, and the CH3 domain. The hinge regions displayed only 71.4% similarity and all of the differences were of a radical nature. The A2 hinge has isoleucine instead of serine at 229, histidine for asparagine at 235, proline for histidine at 238, and cysteine instead of proline in position 234; the latter has the potential for forming an additional interheavy chain disulphide bridge. The occurrence of such a bridge could explain the presence of a pepsin fragment consisting of the hinge region and the Fc. A corresponding fragment is not obtained with the A1 allotype. Both allotypes have a shortened hinge region and a truncated CH2 domain. This feature is characteristic of all reported sequences of IgG2 proteins but not IgG1 in cattle and the goat. This structural feature may be important in subclass-specific recognition by Fc gamma receptors in ruminants. A surprising discovery was the occurrence of five substitutions in the CH3 domain of the IgG2a(A2) in comparison with the A1, which are shared with the CH3 of IgG1. These permit the occurrence of isoallotypic determinants and can explain the difficulty encountered in preparing A2-specific antisera during which adsorption with IgG1 is a routine procedure. The primary sequence data we report confirm the presence of major structural differences between the A allotypes of cattle that was suggested by previous work. The sequence of the A1 allotype most closely agrees with the two IgG2 sequences deduced from their nucleotide sequences whereas the sequence differences in the hinge and C-terminal CH3 make IgG2a(A2) unique. The structural differences between allotypes could have major consequences for such biological activities as phagocytosis, transepithelial transport, lymphocyte and complement activation
— id: 9534, year: 1992, vol: 29, page: 1147, stat: Journal Article,

Franklin's disease: Ig gamma 2 H chain mutant BUR
Prelli F; Frangione B
1992 Feb 1;148(3):949-952, Journal of immunology
The complete sequence of a gamma 2-H chain disease protein BUR is presented. This mutant, a dimer of a 348-residue chain, linked by four disulfide bridges, is composed of a complete V region, hinge, CH2, and CH3 domains. There is one deletion, the CH1 domain, which includes the cysteine residue bridging the H to L chain. Although the V region is encoded by the VHI and JHIII genes, it has several distinctions: methionine at position 11, two unique cysteine residues in the second complementarity determining region (CDR2), and three glycosylation sites, two of which are located in the CDR2 and CDR3 regions. These distinctive characteristics of BUR VH within the framework of a normal VHI may be affected by extensive somatic mutation or by a rare and previously unanalyzed VH gene
— id: 9538, year: 1992, vol: 148, page: 949, stat: Journal Article,

Production of the Alzheimer amyloid beta protein by normal proteolytic processing
Shoji M; Golde TE; Ghiso J; Cheung TT; Estus S; Shaffer LM; Cai XD; McKay DM; Tintner R; Frangione B; et al
1992 Oct 2;258(5079):126-129, Science
The 4-kilodalton (39 to 43 amino acids) amyloid beta protein (beta AP), which is deposited as amyloid in the brains of patients with Alzheimer's diseases, is derived from a large protein, the amyloid beta protein precursor (beta APP). Human mononuclear leukemic (K562) cells expressing a beta AP-bearing, carboxyl-terminal beta APP derivative released significant amounts of a soluble 4-kilodalton beta APP derivative essentially identical to the beta AP deposited in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing full-length beta APP and M17 cells expressing only endogenous beta APP also released soluble 4-kilodalton beta AP, and a similar, if not identical, fragment was readily detected in cerebrospinal fluid from individuals with Alzheimer's disease and normal individuals. Thus cells normally produce and release soluble 4-kilodalton beta AP that is essentially identical to the 4-kilodalton beta AP deposited as insoluble amyloid fibrils in Alzheimer's disease
— id: 9411, year: 1992, vol: 258, page: 126, stat: Journal Article,

Down syndrome as a key to the time sequence of brain changes in Alzheimer disease
Tagliavini F; Giaccone G; Verga L; Frangione B; Bugiani O
1992 ;379:143-158, Progress in clinical & biological research
— id: 9541, year: 1992, vol: 379, page: 143, stat: Journal Article,

A soluble form of prion protein in human cerebrospinal fluid: implications for prion-related encephalopathies
Tagliavini F; Prelli F; Porro M; Salmona M; Bugiani O; Frangione B
1992 May 15;184(3):1398-1404, Biochemical & biophysical research communications
The cellular prion protein (PrPc) is a 33-35 kDa sialoglycoprotein anchored to the external surface of neural and non-neural cells by a glycosyl phosphatidylinositol moiety. In addition, a secretory form of PrPc has been found in cell-free translation systems and in cell cultures. On this basis, we investigated human cerebrospinal fluid for the presence of soluble PrP and identified a protein whose molecular weight, antigenic determinants, N-terminal amino acid sequence and sensitivity to protease digestion corresponded to those of PrPc. In prion-related encephalopathies of humans and animals, the secretory form of PrPc might be converted into the abnormal isoform PrPSc and play a role in the dissemination of the disease process and amyloid formation
— id: 9535, year: 1992, vol: 184, page: 1398, stat: Journal Article,

Amyloid-like fibrils formed in vitro from prion protein segments
Tagliavini, F.; Prelli, F.; Verga, L.; Giaccone, G.; Salmona, M.; Passerini, F.; Wisniewski, T.; Ghetti, B.; Bugiani, O.; Frangione, B.
1992 ;18(1-2):1251-522, Abstracts (Society for Neuroscience)
— id: 97653, year: 1992, vol: 18, page: 1251, stat: Journal Article,

Amyloidoma of the CNS. II. Immunohistochemical and biochemical study
Vidal RG; Ghiso J; Gallo G; Cohen M; Gambetti PL; Frangione B
1992 Oct;42(10):2024-2028, Neurology
We present the immunohistochemical and biochemical identification of an amyloidoma localized to the cerebral white matter in a patient who shows no evidence of systemic or extracranial localized amyloid deposits. Immunohistologic and immunochemical studies, using antibodies against biochemically different amyloid fibrils and amyloid-associated proteins, showed reactivity with antibodies only to lambda light chain and serum amyloid P-component. Amino acid sequence analysis of the purified amyloid fibrils extracted from the brain tumor indicates that the amyloid protein is an unusual immunoglobulin lambda light chain, starting at residue five of the variable domain. These fibrils consist of lambda chain fragments of different lengths (10 to 30 kd) very likely arising by polymerization of the amyloid subunit or sequential proteolytic cleavage of the light chain, or both. After exposure to denaturing agents, the 10-kd subunit retains the characteristics of native amyloid fibrils by electron microscopy
— id: 9412, year: 1992, vol: 42, page: 2024, stat: Journal Article,

Aberrant aggregation of a normal amyloid precursor protein fragment
Wisniewski T; Frangione B
1992 ;3:66-66, Neuroscience facts
— id: 97678, year: 1992, vol: 3, page: 66, stat: Journal Article,

Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid
Wisniewski T; Frangione B
1992 Feb 3;135(2):235-238, Neuroscience letters
Many biochemically diverse proteins can give rise to amyloid fibrils; however, they are all accompanied by P component and glucosaminoglycans. With antibodies specific to apolipoprotein E (apo E) we used immunohistochemical techniques to test for the presence of this protein in both cerebral and systemic amyloid. We found apo E immunoreactivity in all tested types of cerebral and systemic amyloid. In amyloid deposits apo E P, component and glucosaminoglycans may be acting as 'pathological molecular chaperones'. The latter we define as a group of unrelated proteins that induce beta-pleated conformation in amyloidogenic polypeptides
— id: 8466, year: 1992, vol: 135, page: 235, stat: Journal Article,

Molecular biology of Alzheimer's amyloid--Dutch variant
Wisniewski T; Frangione B
1992 Spring;6(1):75-86, Molecular neurobiology
Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) (or familial cerebral amyloid angiopathy) and familial Alzheimer's disease (FAD) share several properties. Both are autosomal dominant forms of cerebral amyloidosis characterized by beta-amyloid (A beta) deposition. In HCHWA-D the A beta is predominantly found in blood vessels and in early parenchymal plaques, whereas in AD parenchymal A beta deposits in the form of senile plaques and neurofibrillary tangles are a more prominent finding. Point mutations in the amyloid precursor protein (APP) have recently been described, in both conditions. A G to C transversion at codon 618 (extracellular portion of APP695), producing a single amino acid substitution of glutamine instead of glutamine acid, occurs in HCHWA-D; whereas mutations at codon 642 in the intramembrane region of APP695 (phenylalanine, isoleucine, or glycine instead of valine) are associated with early onset FAD. This suggests that the site of particular mutations in the APP gene and the type of amino acid substitution in the APP holoprotein are more important in determining clinicopathological phenotype and age at which A beta is deposited. Thus FAD and HCHWA-D can be regarded as two sides of the same coin
— id: 9540, year: 1992, vol: 6, page: 75, stat: Journal Article,

ACCELERATED FIBRILLOGENESIS IN THE DUTCH VARIANT OF ALZHEIMER'S DISEASE
WISNIEWSKI T; GHISO J; FRANGIONE B
1992 ;42(4 SUPPL. 3):304-238, Neurology
— id: 97654, year: 1992, vol: 42, page: 304, stat: Journal Article,

I corpi di Lewy immunoreagiscono con gli anticorpi dell'amiloide di tipo finnico omologo alla gelsolina
Wisniewski T; Haltia M; Ghiso J; Frangione B
1992 ;2:59-60, Update on Parkinson
— id: 102366, year: 1992, vol: 2, page: 59, stat: Journal Article,

Lewy bodies and gelsolin
Wisniewski T; Haltia M; Ghiso J; Frangione B
1992 ;1:6-8, Parkinson/Alzheimer digest
— id: 97677, year: 1992, vol: 1, page: 6, stat: Journal Article,

DNA diagnosis for hereditary cerebral hemorrhage with amyloidosis (Dutch type) [see comments]
Bakker E; van Broeckhoven C; Haan J; Voorhoeve E; van Hul W; Levy E; Lieberburg I; Carman MD; van Ommen GJ; Frangione B; et al
1991 Sep;49(3):518-521, American journal of human genetics
Hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D) is tightly linked to the Alzheimer amyloid precursor protein gene on chromosome 21, which codes for the amyloid beta-protein. A point mutation detected at position 1852 of the amyloid precursor protein gene in four HCHWA-D patients was hypothesized to be the basic defect. This study proves that 22 HCHWA-D patients from three pedigrees all carry this point mutation, whereas the mutation is absent in escapees from the HCHWA-D families as well as in randomly selected Dutch individuals. A mutation-specific oligonucleotide is now available for the confirmation of the HCHWA-D diagnosis. Therefore, presymptomatic testing and prenatal evaluation of individuals at risk in the HCHWA-D families is now feasible
— id: 9543, year: 1991, vol: 49, page: 518, stat: Journal Article,

Alzheimer's disease from the perspective of the systemic and localized forms of amyloidosis
Castano EM; Frangione B
1991 Jul;1(4):263-271, Brain pathology
— id: 7882, year: 1991, vol: 1, page: 263, stat: Journal Article,

Inherited amyloids of the nervous system
Castano EM; Wisniewski T; Frangione B
1991 Oct;1(3):448-454, Current opinion in neurobiology
A diverse group of biochemically distinct proteins give rise to amyloids, each of which is associated with a different disease. These amyloid proteins share numerous properties and typically arise from the abnormal processing of an amyloid precursor protein. The classification, mechanisms and biochemistry of amyloid fibril formation are reviewed here, and two inherited types of amyloid affecting the nervous system are described
— id: 9542, year: 1991, vol: 1, page: 448, stat: Journal Article,

Relationship between non-fibrillary amyloid precursors and cell processes in the cortical neuropil of Alzheimer patients
el Hachimi KH; Verga L; Giaccone G; Tagliavini F; Frangione B; Bugiani O; Foncin JF
1991 Aug 5;129(1):119-122, Neuroscience letters
We examined the ultrastructural localization of amyloid beta-protein in 8 Alzheimer neocortical biopsies. Intense immunoreactivity was located extracellularly on amyloid fibrils and amorphous material. Amorphous labelled material was also found in cell processes. No ultrastructural cell marker, such as glial fibrils, glycogen, tubules, paired helical filaments (PFHs) or synaptic vesicles could be seen in these processes that could allow their identification as glial processes, neurites or presynaptic terminals, respectively; occasional membrane stacks were observed. These findings suggest that preamyloid deposits are related to cell processes and, by elimination, that postsynaptic terminals may be involved in abnormal metabolism of the amyloid fibril precursors
— id: 9544, year: 1991, vol: 129, page: 119, stat: Journal Article,

Codon 618 variant of Alzheimer amyloid gene associated with inherited cerebral hemorrhage
Fernandez-Madrid I; Levy E; Marder K; Frangione B
1991 Nov;30(5):730-733, Annals of neurology
Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) is an autosomal dominant form of severe cerebrovascular amyloid angiopathy causing recurrent strokes during the fifth and sixth decades of life. The major constituent of the amyloid deposits in HCHWA-D is the amyloid beta-protein (A beta), also found in Alzheimer's disease. A point mutation in the DNA sequence encoding A beta has been found in 2 unrelated patients with HCHWA-D, and an assay detecting the single base change was developed for diagnostic purposes. We describe the detection of the point mutation in a patient living in the United States, suffering from recurring cerebral hemorrhages, who only recently was diagnosed with HCHWA-D. In addition, we tested a number of family members, and found the mutation in 2 additional individuals, one of them too young to exhibit clinical manifestations. This study combined with the study of two other families in Holland indicates that the codon 618 variant in the amyloid precursor protein gene segregates with HCHWA-D
— id: 57029, year: 1991, vol: 30, page: 730, stat: Journal Article,

Familial amyloidosis - Finish type - and its relationship to Lewy bodies in Parkinson's and Diffuse Lewy Body disease
Frangione B; Haltia M; Levy E; Ghiso J; Kiuru S; Prelli F; Wisniewski T
Proceedings of the XIth International Congress of Neuropathology, September 2-8, 1990, Kyoto, Japan [Tokyo] : Japanese Society of Neuropathology, 1991,
— id: 4980, year: 1991, vol: , page: 150, stat: Chapter,

Regulation and genetic control of brain amyloid. FESN Study Group
Gajdusek DC; Beyreuther K; Brown P; Cork LC; Cunningham DD; Frangione B; Gibbs CJ Jr; Goldfarb LG; Goldgaber D; Hsiao KK
1991 Jan-Apr;16(1):83-114, Brain research. Brain research reviews
— id: 9549, year: 1991, vol: 16, page: 83, stat: Journal Article,

Immunoreactivity of Alzheimer amyloid precusor protein (APP) specific antisera with platelet granule constituents
Gardella JE; Ghiso J; Gorgone GA; Marratta D; Kaplan AP; Frangione B; Gorevic PD
Amyloid and amyloidosis 1990 Boston : Kluwer, 1991,
— id: 5141, year: 1991, vol: , page: 723, stat: Chapter,

NATURAL-HISTORY OF GERSTMANN-STRAUSSLER-SCHEINKER DISEASE (GSS) IN THE INDIANA KINDRED (IK)
GHETTI, B; FARLOW, MR; FRANGIONE, B; GIACCONE, G; TAGLIAVINI, F; BUGIANI, O
1991 MAY ;50(3):317-317, Journal of neuropathology & experimental neurology
— id: 51595, year: 1991, vol: 50, page: 317, stat: Journal Article,

ALZHEIMER'S AMYLOID PRECURSOR PROTEIN CONTAINS A TETRAPEPTIDE SEQUENCE-RHIDS THAT PROMOTES CELL ADHESION
GHISO J; ROSTAGNO A; FRANGIONE B
1991 ;17(1-2):913-913, Abstracts (Society for Neuroscience)
— id: 101623, year: 1991, vol: 17, page: 913, stat: Journal Article,

Mixed cryoglobulinemia cross-reactive idiotypes: implications for the relationship of MC to rheumatic and lymphoproliferative diseases
Gorevic PD; Frangione B
1991 Apr;28(2):79-94, Seminars in hematology
— id: 9548, year: 1991, vol: 28, page: 79, stat: Journal Article,

Amyloidosis due to a mutation of the gelsolin gene in an American family with lattice corneal dystrophy type II [see comments]
Gorevic PD; Munoz PC; Gorgone G; Purcell JJ Jr; Rodrigues M; Ghiso J; Levy E; Haltia M; Frangione B
1991 Dec 19;325(25):1780-1785, New England journal of medicine
— id: 9416, year: 1991, vol: 325, page: 1780, stat: Journal Article,

Shared gelsolin antigenicity between familial amyloidosis, Finnish type (FAF) and one form of familial lattice corneal dystrophy (LCD) with polyneuropathy from the United States
Gorevic PD; Munoz PC; Rodrigues M; Haltia M; Ghiso J; Frangione B
Amyloid and amyloidosis 1990 Boston : Kluwer, 1991,
— id: 5140, year: 1991, vol: , page: 423, stat: Chapter,

THE PLATELET - A POTENTIAL SOURCE OF AMYLOID PROTEIN IN ALZHEIMERS-DISEASE
GOREVIC, PD; GARDELLA, JE; NEWMAN, PJ; FRANGIONE, B
1991 APR ;39(2):A200-A200, Clinical research
— id: 51606, year: 1991, vol: 39, page: A200, stat: Journal Article,

LATTICE CORNEAL-DYSTROPHY (LCD) TYPE-II - GELSOLIN GENE MUTATION CODON 187 DEMONSTRATED IN AN AMERICAN FAMILY BY PCR AMPLIFICATION AND DNA SEQUENCING
GOREVIO, PD; MUNOZ, PC; GORGONE, G; PURCELL, F; RODRIGUES, M; LEVY, E; FRANGIONE, B
1991 APR ;39(2):A267-A267, Clinical research
— id: 51610, year: 1991, vol: 39, page: A267, stat: Journal Article,

Polymerization of gelsolin variant fragment in tissue causes familial amyloidosis, Finnish type (FAF)
Haltia M; Ghiso J; Prelli F; Levy E; Gallo G; Kiuru S; Somer H; Palo J; Frangione B
Amyloid and amyloidosis 1990 Boston : Kluwer, 1991,
— id: 5142, year: 1991, vol: , page: 409, stat: Chapter,

Gelsolin variant and beta-amyloid co-occur in a case of Alzheimer's with Lewy bodies
Haltia M; Ghiso J; Wisniewski T; Kiuru S; Miller D; Frangione B
1991 Jul-Aug;12(4):313-316, Neurobiology of aging
Familial amyloidosis, Finnish type (FAF), is an autosomal dominant form of amyloidosis which is related to a point mutation in the gelsolin gene localized on chromosome 9. The mutation corresponds to codon 187 of the secreted form of gelsolin, and is expressed in the amyloid fibril at residue 15. Our original FAF patient was demented, and neuropathological analysis showed Alzheimer type brain lesions associated with both classical and cortical Lewy bodies. Furthermore, antiserum against the gelsolin-derived FAF amyloid reacted strongly with both classical and cortical Lewy bodies of this FAF patient. In preliminary experiments similar results were obtained in cases of Parkinson's disease and diffuse Lewy body disease. These observations may indicate a role for gelsolin in the pathogenesis of Parkinson's disease and related conditions
— id: 9421, year: 1991, vol: 12, page: 313, stat: Journal Article,

Isolation and amino terminal sequence of beta-trace, a novel protein from human cerebrospinal fluid
Kuruvilla AP; Hochwald GM; Ghiso J; Castano EM; Pizzolato M; Frangione B
1991 Nov 29;565(2):337-340, Brain research
beta-Trace, a 23.5 kDa glycoprotein of unknown biological functions, is present in all body fluids tested. It is found in higher concentration in human seminal fluid and cerebrospinal fluid (CSF) than in serum. A one-step procedure for the isolation of beta-trace from pooled CSF is described, by affinity chromatography using a specific antibody made against beta-trace. Amino terminal sequence analysis yields the sequence A P E A Q V S V Q P N F Q Q D K F L G with no homology to known proteins, indicating that beta-trace is a novel CSF protein
— id: 9417, year: 1991, vol: 565, page: 337, stat: Journal Article,

The primary structure of the Fab fragment of protein KAU, a monoclonal immunoglobulin M cold agglutinin
Leoni J; Ghiso J; Goni F; Frangione B
1991 Feb 15;266(5):2836-2842, Journal of biological chemistry
The complete amino acid sequence of the Fab fragment of protein KAU, a human monoclonal cold agglutinin (IgMk) with anti-I activity, was determined. The light chain (L-chain) consists of 215 residues; the variable (V)L region belongs to the Hum/Kv325/kIIIb sub-subgroup that is preferentially selected in human IgM autoimmune response. The joining (J) region is encoded by the Jk4 gene, and the constant region (C)L domain expresses the km3 allotypic marker. The Fd fragment contains 232 amino acids, and 120 of them comprise the variable domain. The VH region corresponds to the VHIV subgroup and is closely related to the VHIV 2.1 gene isolated from genomic DNA expressed in peripheral blood of a healthy Caucasian. The complementary-determining region 1 has a unique amino acid (Asp) at position 31, and the complementary-determining region 3 codified by the diversity segment (D) gene, shows poor homology with other known D sequences. The joining segment with two unusual substitutions at the D-J junction is encoded by the JH4 gene. Thus, cold agglutinin KAU is an IgM, VkIIIb-Jk4-km3; VHIV-JH4-C mu
— id: 9424, year: 1991, vol: 266, page: 2836, stat: Journal Article,

Familial Alzheimer's disease
Levy, E; Frangione, B
1991 Oct;1(5):312-314, Current biology. CB
— id: 101675, year: 1991, vol: 1, page: 312, stat: Journal Article,

IMMUNOHISTOCHEMICAL COMPARISON OF EXPERIMENTAL AMYLOIDOSIS IN CLASSICAL, CASEIN-INDUCED, AND ACCELERATED, AMYLOID-ENHANCING-FACTOR-(AEF)-INDUCED, MURINE MODELS
PICKEN, MM; FRANGIONE, B; GALLO, GR
1991 ;64(Suppl 1):A105-A105, Laboratory investigation
— id: 51740, year: 1991, vol: 64, page: A105, stat: Journal Article,

Characterization of high molecular weight amyloid A proteins
Prelli F; Pras M; Shtrasburg S; Frangione B
1991 Jun;33(6):783-786, Scandinavian journal of immunology
Human amyloid A protein (AA) is usually composed of the NH2-terminal 76 amino acid residue of serum amyloid A protein (SAA), although lower and higher molecular weight fragments have been reported. We studied the primary structure of six AA proteins with molecular weights of 11 kDA-15kDA, as determined by SDS-PAGE. Automated Edman degradation of the intact purified proteins and sequence analysis of enzymatic peptides revealed that the AA proteins were composed of only 74 to 87 residues. Moreover, fragments of apolipoprotein E or histones 2a, 3 and 4 were associated with these AA molecules. Thus, AA heterogeneity may reflect diverse processing of the SAA precursor and a very close association with other proteins
— id: 9546, year: 1991, vol: 33, page: 783, stat: Journal Article,

Biochemical studies on the interaction of fibronectin with Ig
Rostagno AA; Frangione B; Gold L
1991 Apr 15;146(8):2687-2693, Journal of immunology
We have previously biochemically characterized three separate sites on the fibronectin (Fn) molecule that interact with IgG. These studies have been extended to examine the interaction of Fn with other classes and subclasses of Ig. By ELISA, a preferential quantitative binding order of Fn to the major Ig classes and subclasses was obtained as follows: IgG greater than IgM greater than IgA, IgG1 greater than IgG3 = IgG4 greater than IgG2, and IgA1 = IgA2. Using fragments of Fn obtained by subtilisin digestion followed by IgM and IgA affinity chromatography, immunoblot analysis using monospecific antisera to separate regions of the Fn molecule, and amino acid sequence analysis, these studies indicate that polyclonal IgA and IgM interact with Fn in the same three regions and under the same ionic conditions as previously described for IgG. Site 1 is a 22-kDa fragment that commences at residue 1 of the Fn molecule. Sites 2 (16 kDa) and 3 (26-29 kDa) begin at residues 588 and 1597, respectively. Under physiological conditions a monoclonal antibody that recognizes site 1 completely inhibited the interaction of intact Fn with IgG, IgM, and IgA. Therefore, this is the only physiologically active site in the intact molecule. Aggregated but not monomeric IgG competitively inhibited the binding of Fn to IgG-coated microtiter ELISA plates; thus, this interaction can take place in a fluid-phase system. These results indicate that Fn can potentially interact with immune complexes and aggregates of all Ig in the circulation and thus may play a significant role in both their clearance and deposition in Fn-containing tissues, such as occurs in immune-complex-related disorders
— id: 9547, year: 1991, vol: 146, page: 2687, stat: Journal Article,

Alzheimer patients: preamyloid deposits are immunoreactive with antibodies to extracellular domains of the amyloid precursor protein
Tagliavini F; Giaccone G; Verga L; Ghiso J; Frangione B; Bugiani O
1991 Jul 8;128(1):117-120, Neuroscience letters
In patients with Alzheimer's disease, in patients with Down's syndrome and in aged non-demented individuals, anti-beta-protein antibodies label not only the fibrillary amyloid, but also preamyloid deposits. The latter are made up of amorphous material lacking the tinctorial, optical and ultrastructural properties of amyloid fibrils. To investigate the antigenic profile of preamyloid deposits, we have carried out an immunohistochemical study on specimens of cerebral cortex from 4 Alzheimer patients and two non-demented individuals, using antibodies to the beta-protein (anti-SP28), the C-terminal region of the amyloid precursor protein (APP) (anti-SP20) and an APP extracellular epitope between residues 50 and 100 (anti-preA4). Anti-preA4 and anti-SP28 immunoreactivity was found to be present in preamyloid deposits, whereas anti-SP20 immunoreactivity was not. These findings suggest that an extracellular portion of APP, close to the N-terminus of the molecule, participates with beta-protein in the composition of preamyloid deposits
— id: 9420, year: 1991, vol: 128, page: 117, stat: Journal Article,

Amyloid protein of Gerstmann-Straussler-Scheinker disease (Indiana kindred) is an 11 kd fragment of prion protein with an N-terminal glycine at codon 58
Tagliavini F; Prelli F; Ghiso J; Bugiani O; Serban D; Prusiner SB; Farlow MR; Ghetti B; Frangione B
1991 Mar;10(3):513-519, EMBO journal
Gerstmann-Straussler-Scheinker (GSS) disease is a familial neurological disorder pathologically characterized by amyloid deposition in the cerebrum and cerebellum. The GSS amyloid is immunoreactive to antisera raised against the hamster prion protein (PrP) 27-30. This is a proteinase K-resistant glycoprotein of 27-30 kd that is derived from an abnormal isoform of a neuronal glycoprotein of 33-35 kd designated PrPSc and is a molecular marker of amyloid fibrils isolated from animals with scrapie and humans with related disorders. We have purified and characterized proteins extracted from amyloid plaque cores isolated from two patients of the Indiana kindred of GSS disease. We found that the major component of GSS amyloid is an 11 kd degradation product of PrP, whose N-terminus corresponds to the glycine residue at position 58 of the amino acid sequence deduced from the human PrP cDNA. In addition, amyloid fractions contained larger PrP fragments with apparently intact N-termini and amyloid P component. These findings suggest that the disease process leads to proteolytic cleavage of PrP, generating an amyloidogenic peptide that polymerizes into insoluble fibrils. The N-terminal cleavage of PrP in GSS disease occurs at a tryptophan-glycine peptide bond identical to that cleaved by proteinase K in vitro to generate PrP 27-30 from hamster PrPSc at codon 90. Since no mutations of the structural PrP gene have been found in the Indiana family of GSS disease, it is conceivable that factors other than the primary structure of PrP play a crucial role in the process of amyloid formation and the development of clinical neurologic dysfunction
— id: 9423, year: 1991, vol: 10, page: 513, stat: Journal Article,

Nodular cutaneous amyloidosis
Trau H; Shpiro D; Schewach-Millet M; Pras M; Prelli F; Frangione B
1991 Aug;13(4):414-417, American journal of dermatopathology
A nodular cutaneous amyloidosis biopsy specimen from a solitary nodule of a 75-year-old patient was characterized by amino terminal sequence analysis and was proved to be derived from immunoglobulin kIII light chain. Five years after the diagnosis of amyloidosis in the skin was made, a rectal biopsy demonstrated amyloid deposits in a blood vessel. It is suggested that nodular cutaneous amyloidosis is a slowly progressive systemic disease of the AL type, that manifest itself mainly in the skin
— id: 9545, year: 1991, vol: 13, page: 414, stat: Journal Article,

DNA-DIAGNOSIS FOR HEREDITARY CEREBRAL-HEMORRHAGE WITH AMYLOIDOSIS (DUTCH) BY SSCP-ANALYSIS
VOORHOEVE, E; HAAN, J; VEGTERVANDERVLIS, M; VANBROECKHOVEN, C; VANOMMEN, GJB; FRANGIONE, B; ROOS, RAC; BAKKER, E
1991 OCT ;49(4):182-182, American journal of human genetics
— id: 51529, year: 1991, vol: 49, page: 182, stat: Journal Article,

Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation
Wisniewski T; Ghiso J; Frangione B
1991 Nov 14;180(3):1528-1528, Biochemical & biophysical research communications
— id: 9418, year: 1991, vol: 180, page: 1528, stat: Journal Article,

Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation [published erratum appears in Biochem Biophys Res Commun 1991 Nov 14;180(3):1528]
Wisniewski T; Ghiso J; Frangione B
1991 Sep 30;179(3):1247-1254, Biochemical & biophysical research communications
beta-Amyloid (A beta) deposition in fibril form is the central event in a number of diseases, including Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D). A beta is produced by degradation of a larger amyloid precursor protein (APP). Recently a mutation in the APP gene has been found in HCHWA-D causing a glutamine for glutamic acid substitution at residue 22 of A beta. The influence of this mutation on fibrillogenesis is not known, although it is clear that affected patients have accelerated cerebrovascular amyloid deposition, with disease symptoms early in life. We report the in vitro demonstration of accelerated fibril formation in a 28 residue synthetic peptide homologous to the Dutch variant A beta. Furthermore, in eight residue peptides homologous to A beta the presence of the mutation is necessary for fibril formation. These findings provide a mechanism for accelerated amyloid formation in the Dutch variant of APP
— id: 9419, year: 1991, vol: 179, page: 1247, stat: Journal Article,

LEWY BODIES ARE IMMUNOREACTIVE WITH ANTIBODIES RAISED TO GELSOLIN AMYLOID
WISNIEWSKI T; HALTIA M; GHISO J; FRANGIONE B
1991 ;41(3 SUPPL. 1):177-316, Neurology
— id: 97655, year: 1991, vol: 41, page: 177, stat: Journal Article,

Lewy bodies are immunoreactive with antibodies raised to gelsolin related amyloid-Finnish type
Wisniewski T; Haltia M; Ghiso J; Frangione B
1991 May;138(5):1077-1083, American journal of pathology
Lewy bodies (LB) are intraneuronal, cytoplasmic inclusion bodies. They are invariably present in Parkinson's and diffuse LB diseases. Their composition by direct biochemical methods is unknown, although LBs are immunoreactive with a number of antibodies, including anti-ubiquitin and anti-neurofilament antibodies. Familial amyloidosis, Finnish type (FAF), is an autosomal-dominant form of systemic amyloidosis. The authors have isolated and partially sequenced the amyloid. The protein has significant sequence identity with gelsolin, an actin-modulating protein. Rabbit polyclonal antibodies raised to the FAF amyloid not only immunostain the amyloid but also LBs in the cortex and substantia nigra of Parkinson's and diffuse LB disease brains. Immunoreactivity is absorbed by the purified amyloid but is unaffected by ubiquitin. This provides a link between the LB and one of the human amyloidoses, FAF
— id: 9422, year: 1991, vol: 138, page: 1077, stat: Journal Article,

Human rheumatoid factor cross-idiotypes. III. Bla monoclonal rheumatoid factor, prototype of the BLA cross-idiotype group, has distinct kappa chains related to the V kappa III subgroup and VH4 heavy chains [see comments]
Barnes JL; Goni F; Heyermann H; Frangione B; Agnello V
1990 Nov;33(11):1710-1715, Arthritis & rheumatism
The BLA cross-idiotype (XId) is present on a unique subset of rheumatoid factors (RF) that cross-react with DNA-histone. In this study, prototype Bla monoclonal RF was shown from serologic investigations and N-terminal amino acid sequence analysis to have distinct kappa chains related to the V kappa III subgroup and VH4 heavy chains. The amino terminus of the heavy chain was cyclized, rendering the protein resistant to Edman degradation and providing a possible investigator bias to the published Ig sequence data to date. This appears to be the first definitive report of a serum IgM that expresses the VH4 gene. RF with DNA cross-reactivity have been reported to be produced by human and mouse cloned cells that have the VH4 or homologous mouse Vh36-60 gene
— id: 9550, year: 1990, vol: 33, page: 1710, stat: Journal Article,

Alzheimer patients and Down patients: abnormal presynaptic terminals are related to cerebral preamyloid deposits
Bugiani O; Giaccone G; Verga L; Pollo B; Ghetti B; Frangione B; Tagliavini F
1990 Oct 30;119(1):56-59, Neuroscience letters
In Alzheimer's disease, in Down syndrome and in normal aging, scattered deposits of amyloid fibril precursors occur in both cerebral cortex and subcortical grey structures. Within such preamyloid deposits, no degenerating neurites with paired helical filaments have ever been observed. This study, carried out on brains from Alzheimer patients and Down patients, reports on the relationship between preamyloid deposits and neuritic changes. These changes were represented by presynaptic terminal swellings immunolabeled by antisynaptophysin and antiubiquitin antibodies, not by Alz50. These findings support the view that the deposition of amyloid fibril precursors in the neuropil is closely related to presynaptic terminals, although whether the former precedes or follows the development of presynaptic terminal changes is still undetermined
— id: 9551, year: 1990, vol: 119, page: 56, stat: Journal Article,

CEREBRAL PREAMYLOID DEPOSITS AND CONGOPHILIC ANGIOPATHY IN AGED DOGS
Bugiani, O; Verga, L; Tagliavini, F; Pollo, B; Finazzi, M; Frangione, B; Giaccone, G
1990 May;49(3):331-331, Journal of neuropathology & experimental neurology
— id: 31945, year: 1990, vol: 49, page: 331, stat: Journal Article,

SYNAPTIC ALTERATIONS IN PREAMYLOID DEPOSITS
Bugiani, O; Verga, L; Tagliavini, F; Pollo, B; Ghetti, B; Frangione, B; Giaccone, G
1990 May-Jun;11(3):310-310, Neurobiology of aging
— id: 31943, year: 1990, vol: 11, page: 310, stat: Journal Article,

COOCCURRENCE OF 2 AMYLOID PROTEINS, GELSOLIN AND BETA-PROTEIN, IN A PATIENT WITH FAMILIAL AMYLOIDOSIS, FINNISH TYPE, AND ALZHEIMERS-DISEASE
Frangione, B; Haltia, M; Ghiso, J; Kiuru, S; Prelli, F
1990 May-Jun;11(3):300-300, Neurobiology of aging
— id: 31940, year: 1990, vol: 11, page: 300, stat: Journal Article,

Intact Alzheimer amyloid precursor protein (APP) is present in platelet membranes and is encoded by platelet mRNA
Gardella JE; Ghiso J; Gorgone GA; Marratta D; Kaplan AP; Frangione B; Gorevic PD
1990 Dec 31;173(3):1292-1298, Biochemical & biophysical research communications
Using antibodies directed against N-terminal and C-terminal epitopes we have immunologically detected APP species in the membrane and saline-soluble fractions of unstimulated platelets, and in the conditioned medium of thrombin-stimulated platelets. These studies demonstrate an intact 140 kD membrane-associated form of APP that is released on degranulation. Evidence that platelets synthesize at least one form of APP (APP751) was obtained by enzymatic amplification of specific mRNA using Polymerase Chain Reaction (PCR) and direct sequence analysis of PCR product. Processing of APP for release may occur via successive C-terminal truncations, and/or by the release and proteolysis of an intact membrane associated form. An intact form of APP in platelets provides a circulating substrate upon which proteases from many tissues may act to produce beta protein (AB) during pathologic conditions
— id: 9425, year: 1990, vol: 173, page: 1292, stat: Journal Article,

Gelsolin variant (Asn-187) in familial amyloidosis, Finnish type
Ghiso J; Haltia M; Prelli F; Novello J; Frangione B
1990 Dec 15;272(3):827-830, Biochemical journal
Familial amyloidosis, Finnish type (FAF), is an inherited form of systemic amyloidosis clinically characterized by cranial neuropathy and lattice corneal dystrophy. We have demonstrated that the protein subunit isolated from amyloid fibrils shows considerable sequence identity with gelsolin, an actin-binding protein. We have purified the amyloid subunit from a second case and further analysed different fractions from the previous one. Sequence analysis shows that, in both cases, the amyloid subunit starts at position 173 of the mature molecule; it has a heterogeneous N-terminus and contains one amino acid substitution, namely asparagine for aspartic acid, at position 15 (gelsolin residue 187), that is due to a guanine-to-adenine transversion corresponding to nucleotide-654 of human plasma gelsolin cDNA. The substitution maps in a fragment with actin-binding activity and is located in a repetitive motif highly conserved among species. Thus FAF is the first human disease known to be caused by an internal abnormal degradation of a gelsolin variant. We designate this variant of gelsolin-associated amyloidosis 'Agel Asn-187'
— id: 9426, year: 1990, vol: 272, page: 827, stat: Journal Article,

Binding of cystatin C to C4: the importance of sense-antisense peptides in their interaction
Ghiso J; Saball E; Leoni J; Rostagno A; Frangione B
1990 Feb;87(4):1288-1291, Proceedings of the National Academy of Sciences of the United States of America
Hydropathic anticomplementarity of amino acids indicates that peptides derived from complementary DNA strands may form amphiphilic structures and bind one another. By using this concept, we have found that the antisense peptide Ser-Tyr-Asp-Leu complementary to the segment Gln-Ile-Val-Ala-Gly (residues 55-59) in cystatin C (an inhibitor of cysteine proteases) is located at positions 611-614 of the beta chain of human C4, the fourth component of complement. Here we describe and characterize the specific interaction between cystatin C and C4 by ligand affinity chromatography and ELISA. Interaction between the two native proteins was mimicked on replacement of one of them with the corresponding sense-antisense peptide coupled to a carrier protein, and the binding was inhibited by these synthetic peptides in solution. Through the interaction with C4, cystatin C may play a regulatory role in complement activation that might be of particular importance at tissue sites where both proteins are produced by macrophages
— id: 9432, year: 1990, vol: 87, page: 1288, stat: Journal Article,

Neurofibrillary tangles of the Indiana kindred of Gerstmann-Straussler-Scheinker disease share antigenic determinants with those of Alzheimer disease
Giaccone G; Tagliavini F; Verga L; Frangione B; Farlow MR; Bugiani O; Ghetti B
1990 Oct 22;530(2):325-329, Brain research
In the Indiana kindred of Gerstmann-Straussler-Scheinker disease, neurofibrillary tangles (NFT) with paired helical filaments (PHF) are numerous, widespread and consistently present in the cerebral cortex and several subcortical nuclei. Such tangles share antigenic determinants with those of Alzheimer disease; in fact, they are recognized by Alz50, anti-PHF and anti-ubiquitin antibodies. Thus, NFT with structural and immunocytochemical similarities are present in two distinct forms of amyloidosis of the central nervous system, i.e. the Indiana kindred of Gerstmann-Straussler-Scheinker disease and Alzheimer disease
— id: 9552, year: 1990, vol: 530, page: 325, stat: Journal Article,

Cerebral preamyloid deposits and congophilic angiopathy in aged dogs
Giaccone G; Verga L; Finazzi M; Pollo B; Tagliavini F; Frangione B; Bugiani O
1990 Jul 3;114(2):178-183, Neuroscience letters
The brains of 7 dogs aged 6 to 18 years have been histochemically and immunohistochemically investigated at the light- and electron microscopy levels for preamyloid deposits and amyloid fibrils to verify the hypothesis that the accumulation of cleavage products of amyloid precursor protein is related not only to Alzheimer's disease but also to the normal aging of the brain. Preamyloid deposits were detected in the neuropil of the cerebral cortex and neostriatum, whereas amyloid fibrils were found in the walls of parenchimal and leptomeningeal vessels. The densities of preamyloid deposits in the neuropil and of deposits of amyloid fibrils in the vessel walls were higher in the brains of the most aged dogs. These findings suggest that aging of the canine brain is characterized by an accumulation of intermediate cleavage products of the amyloid precursor protein in both the neuropil and the vessel walls, and by processing of these products to amyloid fibrils in the vessel walls
— id: 9556, year: 1990, vol: 114, page: 178, stat: Journal Article,

NEUROFIBRILLARY TANGLES IN THE INDIANA KINDRED OF GERSTMANN- STRAUSSLER-SCHEINKER DISEASE SHARE ANTIGENIC DETERMINANTS WITH THOSE OF ALZHEIMER-DISEASE
Giaccone, G; Tagliavini, F; Verga, L; Frangione, B; Farlow, MR; Bugiani, O; Ghetti, B
1990 May-Jun;11(3):280-280, Neurobiology of aging
— id: 31939, year: 1990, vol: 11, page: 280, stat: Journal Article,

Amyloid in familial amyloidosis, Finnish type, is antigenically and structurally related to gelsolin
Haltia M; Ghiso J; Prelli F; Gallo G; Kiuru S; Somer H; Palo J; Frangione B
1990 Jun;136(6):1223-1228, American journal of pathology
Immunohistochemical studies of six patients with familial amyloidosis, Finnish type, showed that their amyloid deposits did not react with polyclonal antibodies against the amyloid proteins of other, established forms of systemic or cerebral amyloidosis. However, strong immunoreactivity was observed with rabbit antiserum raised against a low molecular weight purified amyloid subunit isolated from one of the patients. This immunoreactivity was abolished by absorption with the low molecular weight amyloid fraction. The amino terminal sequence of the amyloid protein subunit was homologous to gelsolin, an actin-modulating protein, and the amyloid deposits in tissues reacted with a monoclonal antibody against gelsolin. These studies show that the amyloid protein in familial amyloidosis, Finnish type, is not related to previously identified forms of amyloid, including prealbumin (transthyretin) variants, but represents a novel amyloidogenic protein related to gelsolin, a plasma and cytoplasmic protein
— id: 9429, year: 1990, vol: 136, page: 1223, stat: Journal Article,

Amyloid protein in familial amyloidosis (Finnish type) is homologous to gelsolin, an actin-binding protein
Haltia M; Prelli F; Ghiso J; Kiuru S; Somer H; Palo J; Frangione B
1990 Mar 30;167(3):927-932, Biochemical & biophysical research communications
Familial amyloidosis, Finnish type, is clinically characterized by cranial neuropathy and lattice corneal dystrophy. It is an autosomal dominant form of systemic amyloidosis with small deposits of congophilic material occurring in most tissues, particularly in association with blood vessel walls and basement membranes. Amyloid fibrils were extracted from the kidney of patient VUO, and rabbit antiserum raised against the 12 kDa purified amyloid subunit displayed strong immunohistochemical reactivity with the amyloid deposits. The amino terminal sequence of this 12 kDa amyloid protein (ATEVPVSWESFNNGD) showed homology with gelsolin (or actin depolymerizing factor), a 93 kDa plasma protein. The amyloid peptide is a degradation product, starting at position 173, of the gelsolin molecule
— id: 9431, year: 1990, vol: 167, page: 927, stat: Journal Article,

Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type
Levy E; Carman MD; Fernandez-Madrid IJ; Power MD; Lieberburg I; van Duinen SG; Bots GT; Luyendijk W; Frangione B
1990 Jun 1;248(4959):1124-1126, Science
An amyloid protein that precipitates in the cerebral vessel walls of Dutch patients with hereditary cerebral hemorrhage with amyloidosis is similar to the amyloid protein in vessel walls and senile plaques in brains of patients with Alzheimer's disease, Down syndrome, and sporadic cerebral amyloid angiopathy. Cloning and sequencing of the two exons that encode the amyloid protein from two patients with this amyloidosis revealed a cytosine-to-guanine transversion, a mutation that caused a single amino acid substitution (glutamine instead of glutamic acid) at position 22 of the amyloid protein. The mutation may account for the deposition of this amyloid protein in the cerebral vessel walls of these patients, leading to cerebral hemorrhages and premature death
— id: 8382, year: 1990, vol: 248, page: 1124, stat: Journal Article,

Mutation in gelsolin gene in Finnish hereditary amyloidosis
Levy E; Haltia M; Fernandez-Madrid I; Koivunen O; Ghiso J; Prelli F; Frangione B
1990 Dec 1;172(6):1865-1867, Journal of experimental medicine
Familial amyloidosis, Finnish type (FAF), is an autosomal dominant form of familial amyloid polyneuropathy. The novel amyloid fibril protein found in these patients is a degradation fragment of gelsolin, an actin-binding protein. We found a mutation (adenine for guanine) at nucleotide 654 of the gelsolin gene in genomic DNA isolated from five FAF patients. This site is polymorphic since the normal allele was also present in all the patients tested. This mutation was not found in two unaffected family members and 11 normal controls. The A for G transition causes an amino acid substitution (asparagine for aspartic acid) that was found at position 15 of the amyloid protein. The mutation and consequent amino acid substitution may lead to the development of FAF
— id: 9427, year: 1990, vol: 172, page: 1865, stat: Journal Article,

MUTATION IN THE ALZHEIMERS-DISEASE AMYLOID GENE IN PATIENTS WITH HEREDITARY CEREBRAL-HEMORRHAGE WITH AMYLOIDOSIS - DUTCH TYPE
Levy, E; Carman, MD; Fernandezmadrid, IJ; Lieberburg, I; Power, MD; Vanduinen, SG; Bots, GTAM; Luyendijk, W; Frangione, B
1990 May-Jun;11(3):300-300, Neurobiology of aging
— id: 31941, year: 1990, vol: 11, page: 300, stat: Journal Article,

The complete amino acid sequence of toxin TsTX-VI isolated from the venom of the scorpion Tityus serrulatus
Marangoni S; Ghiso J; Sampaio SV; Arantes EC; Giglio JR; Oliveira B; Frangione B
1990 Oct;9(5):595-601, Journal of protein chemistry
The complete sequence of the toxin TsTX-VI from the venom of the scorpion Tityus serrulatus Lutz and Mello is presented. The sequence has been determined by automated Edman analysis of the reduced and carboxymethylated protein as well as of the resulting peptides, obtained from S. aureus protease and tryptic digestions. TsTX-VI is composed of 62 residues and has a calculated molecular weight of 6717. Homology studies with other scorpion toxins show that TsTX-VI is more similar to the Old World than to the North American scorpion toxins. The hydropathic index indicates that TsTX-VI is more hydrophobic than Ts-gamma. Toxicity studies carried out in mice demonstrate that i.v. injection of TsTX-VI is unable to evoke the usual symptoms induced by the typical neurotoxins of this venom, but only a generalized allergic reaction. These properties are important in clarifying the relationship between primary structure and biological function of scorpion toxins
— id: 9428, year: 1990, vol: 9, page: 595, stat: Journal Article,

Amyloid enhancing factor and inflammatory reaction
Picken MM; Gallo GR; Frangione B
1990 Oct;63(4):586-587, Laboratory investigation
— id: 9554, year: 1990, vol: 63, page: 586, stat: Journal Article,

Biochemical characterization of amyloid derived from the variable region of the kappa light chain subgroup III
Picken MM; Gallo GR; Pruzanski W; Frangione B
1990 Jun;33(6):880-884, Arthritis & rheumatism
We report the clinical data and results of biochemical studies of amyloid in a postpartum patient. The amyloidosis was not associated with myeloma, and immunopathologic examination of the amyloid deposits gave inconclusive results. Biochemical analysis of the deposits proved that the amyloid protein JUN was derived from the variable region of the kappa light chain subgroup III and is homologous to a rarely expressed protein POM, which was previously shown to have rheumatoid factor activity. The significance of this association and the diagnostic problems associated with certain cases of amyloid derived from immunoglobulin light chain (type AL) are discussed
— id: 9557, year: 1990, vol: 33, page: 880, stat: Journal Article,

Distribution of the protease inhibitor alpha 1-antichymotrypsin in cerebral and systemic amyloid
Picken MM; Larrondo-Lillo M; Coria F; Gallo GR; Shelanski ML; Frangione B
1990 Jan;49(1):41-48, Journal of neuropathology & experimental neurology
We performed immunocytochemical staining to study the distribution of serum protease inhibitors in cerebral and systemic amyloid deposits. In beta-protein amyloid deposits in Alzheimer's disease, Down's syndrome, age-related cerebral amyloidosis, sporadic cerebral amyloid angiopathy and hereditary cerebral hemorrhage with amyloidosis of Dutch origin, antibody to alpha 1-antichymotrypsin (ACT) stains senile plaques and vascular deposits. Immature plaques or preamyloid deposits, identified by their positive staining for beta-protein and negative staining for Congo red, which represents the earliest recognizable stages of amyloid deposition, are also labeled. We did not detect ACT in other chemically different forms of cerebral and systemic amyloid. None of the other inhibitors in this study, i.e. antithrombin III and alpha 2-macroglobulin, was detected in the amyloid deposits. Neurons and glial cells throughout the central nervous system in normal and amyloid-containing brains also bind ACT antibody. The results emphasize the close association of ACT with one type of cerebral amyloid (beta-amyloid diseases) as well as the failure to detect such an association in other chemically different forms of cerebral and systemic amyloids
— id: 9558, year: 1990, vol: 49, page: 41, stat: Journal Article,

Expression of a normal and variant Alzheimer's beta-protein gene in amyloid of hereditary cerebral hemorrhage, Dutch type: DNA and protein diagnostic assays
Prelli F; Levy E; van Duinen SG; Bots GT; Luyendijk W; Frangione B
1990 Jul 16;170(1):301-307, Biochemical & biophysical research communications
Amyloid fibrils deposited in cerebral vessel walls in Dutch patients with hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) are formed by polymerization of a 39-residue peptide similar to the beta-protein of Alzheimer's disease, Down syndrome, sporadic cerebral amyloid angiopathy and normal aging. Sequence analysis of genomic DNA in HCHWA-D patients demonstrated a point mutation, cytosine for guanine at position 1852 of the precursor beta-protein gene, which causes a single amino acid substitution (glutamine for glutamic acid) corresponding to position 22 of the amyloid protein. The normal allele was also present in these patients. To examine the expression of normal and variant beta-protein alleles in HCHWA-D we analyzed all the tryptic peptides obtained from several amyloid fractions from leptomeningeal vascular walls. Amino acid sequence of two peptides (T3a and T3b) with identical amino acid composition revealed that T3a had glutamine and T3b had glutamic acid at position 22. Thus both the normal and variant Alzheimer's beta-protein alleles are expressed in vascular amyloid in HCHWA-D and may be detected by tryptic peptide mapping. Moreover, we have developed a diagnostic assay for high risk populations and prenatal evaluation that is based on the existence of the mutation
— id: 9555, year: 1990, vol: 170, page: 301, stat: Journal Article,

Coexistence of Alzheimer's amyloid precursor protein and amyloid protein in cerebral vessel walls
Tagliavini F; Ghiso J; Timmers WF; Giaccone G; Bugiani O; Frangione B
1990 Jun;62(6):761-767, Laboratory investigation
Polyclonal antibodies to synthetic peptides homologous to amino acid residues 45-62, 597-624, and 676-695 of the predicted sequence of Alzheimer's amyloid precursor protein (APP) were used to investigate the site of origin of APP, and the relationship between APP and amyloid protein in Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D). Cortical sections as well as homogenates of isolated leptomeningeal and cortical microvessels from three patients with AD, two patients with HCHWA-D, and two nondemented controls were probed. In vessel extracts of both groups of patients and the controls, APP was detected as a set of proteins with electrophoretic mobility of 105 to 135 kilodaltons. In cortical sections of all subjects, APP immunoreactivity was found in leptomeningeal and cortical vessel walls. In patients with AD and HCHWA-D, APP and amyloid fibrils coexisted in the same vessels. Moreover, APP immunoreactivity was found in association with 50% of senile plaques in AD brains, but was not evidenced in parenchymal amyloid deposits in patients with HCHWA-D. These data suggest that the vascular system is a source of APP and that the processing of APP into insoluble fibrils in AD and HCHWA-D may take place in situ
— id: 9430, year: 1990, vol: 62, page: 761, stat: Journal Article,

ALZHEIMERS-DISEASE AND HEREDITARY (DUTCH-TYPE) CEREBRAL- HEMORRHAGE - COEXISTENCE OF AMYLOID PRECURSOR PROTEIN AND AMYLOID PROTEIN IN CEREBRAL VESSEL WALLS
Tagliavini, F; Ghiso, J; Timmers, WF; Giaccone, G; Bugiani, O; Frangione, B
1990 May;49(3):332-332, Journal of neuropathology & experimental neurology
— id: 31946, year: 1990, vol: 49, page: 332, stat: Journal Article,

INDIANA KINDRED OF GERSTMANN-STRAUSSLER-SCHEINKER DISEASE - ISOLATION OF LOW-MOLECULAR-WEIGHT PROTEIN FROM AMYLOID PLAQUE CORES
Tagliavini, F; Prelli, F; Ghiso, J; Bugiani, O; Farlow, MR; Ghetti, B; Frangione, B
1990 May-Jun;11(3):304-304, Neurobiology of aging
— id: 31942, year: 1990, vol: 11, page: 304, stat: Journal Article,

Parenchymal preamyloid and amyloid deposits in the brains of patients with hereditary cerebral hemorrhage with amyloidosis--Dutch type
Timmers WF; Tagliavini F; Haan J; Frangione B
1990 Oct 16;118(2):223-226, Neuroscience letters
Hereditary cerebral hermorrhage with amyloidosis--Dutch type, one of the 'cerebral beta-amyloid diseases', like Alzheimer's disease, is characterized by extensive deposition of amyloid in small cerebral vessels. We investigated the presence of parenchymal beta-protein deposits in two Dutch patients with hereditary cerebral hemorrhage with amyloidosis. Immunostaining with anti-SP28 revealed a full spectrum of these deposits, varying from preamyloid deposits to burned-out plaques. However, their density is less than in