Thomas M. Wisniewski

Styryl-based and tricyclic compounds as potential anti-prion agents
Chung, Erika; Prelli, Frances; Dealler, Stephen; Lee, Woo Sirl; Chang, Young-Tae; Wisniewski, Thomas
2011 ;6(9):e24844-e24844, PLoS ONE
Prion diseases currently have no effective therapy. These illnesses affect both animal and human populations, and are characterized by the conformational change of a normal self protein PrP(C) (C for cellular) to a pathological and infectious conformer, PrP(Sc) (Sc for scrapie). We used a well characterized tissue culture model of prion infection, where mouse neuroblastoma cells (N2a) were infected with 22L PrP(Sc), to screen compounds for anti-prion activity. In a prior study we designed a library of styryl based, potential imaging compounds which were selected for high affinity binding to Alzheimer's disease beta-amyloid plaques and good blood-brain barrier permeability. In the current study we screened this library for activity in the N2a/22L tissue culture system. We also tested the anti-prion activity of two clinically used drugs, trimipramine and fluphenazine, in the N2a/22L system. These were selected based on their structural similarity to quinacrine, which was previously reported to have anti-prion activity. All the compounds were also screened for toxicity in tissue culture and their ability to disaggregate amyloid fibrils composed of PrP and beta-amyloid synthetic peptides in vitro. Two of the imaging agents, 23I and 59, were found to be both effective at inhibiting prion infection in N2a/22L tissue culture and to be non-toxic. These two compounds, as well as trimipramine and fluphenazine were evaluated in vivo using wild-type CD-1 mice infected peripherally with 139A PrP(Sc). All four agents significantly prolonged the asymptomatic incubation period of prion infection (p<0.0001 log-rank test), as well as significantly reducing the degree of spongiform change, astrocytosis and PrP(Sc) levels in the brains of treated mice. These four compounds can be considered, with further development, as candidates for prion therapy
— id: 137851, year: 2011, vol: 6, page: e24844, stat: Journal Article,

Dissolution of Pre-Existing Platelet Thrombus by Synergistic Administration of Low Concentrations of Bifunctional Antibodies against beta3 Integrin
Dang, Suying; Hong, Tao; Wisniewski, Thomas; Zhang, Wei
2011 ;6(10):e27012-e27012, PLoS ONE
Most antithrombotic approaches target prevention rather than the more clinically relevant issue of resolution of an existing thrombus. In this study, we describe a novel and effective therapeutic strategy for ex vivo clearance of pre-existing platelet thrombus by the combination of two bifunctional platelet GPIIIa49-66 ligands that target different parts of the arterial thrombus. We produced an additional GPIIIa49-66 agent (named APAC), which homes to activated platelets. Like our previously described SLK (which targets newly deposited fibrin strands surrounding the platelet thrombus), APAC destroys platelet aggregates ex vivo in an identical fashion with 85% destruction of platelet aggregates at 2 hours. The combined application of APAC and SLK demonstrated a approximately 2 fold greater platelet thrombus dissolution than either agent alone at a low concentration (0.025 microM). Platelet-rich clot lysis experiments demonstrated the time required for 50% platelet-rich fibrin clot lysis (T(50%)) by APAC (95+/-6.1 min) or SLK (145+/-7.1 min) was much longer than that by combined APAC+SLK (65+/-7.6 min) at the final concentration of 0.025 microM (APAC+SLK vs APAC, p<0.05; APAC+SLK vs SLK, p<0.01). Thus these low concentrations of a combination of both agents are likely to be more effective and less toxic when used therapeutically in vivo
— id: 141502, year: 2011, vol: 6, page: e27012, stat: Journal Article,

Induction of TLR9 signaling in 3XTG-ad mice
Scholtzova H.; Goni F.; Sun Y.; Hatos L.; Pan J.; Kascsak R.; Mehta P.; Spinner D.; Wisniewski T.
2011 ;7(4 SUPPL 1):S665-S665, Alzheimer's & Dementia
Background: Manipulation of the immune system is becoming increasingly important for the potential treatment of Alzheimer's disease (AD). However, problems in the initial human clinical trials have included toxicity from excessive cell mediated immunity, hemorrhages and limited cognitive benefits. Our research group postulated stimulation of innate immunity, via the Toll-like receptors (TLRs), as an alternative approach to overcome these side effects. Our prior work in prion disease, suggested TLR9 to be an attractive candidate for AD prevention and therapy. We sought to determine the effectiveness of TLR9 stimulation on both amyloid and tau related pathology. Various CpG DNA drugs that are TLR9 agonist are safe in humans and rodents. Methods: We utilized type B CpG oligodeoxynucleotides (ODNs) to stimulate innate immunity in 3xTg-AD mice, which develop both plaque and tangle pathology. The mice were divided into 2 study groups treated from 11 to 17 months and from 7 to 20 months of age. After the treatment, the mice were subjected to behavioral testing. In addition, we tested the effect of the TLR9 agonist CpG ODN on microglial As42 uptake and degradation in culture. Results: The transgenic mice were less active than their mu/d-littermates, but no significant differences between Tg groups were found in any of the locomotor parameters. CpG ODN treatment led to working memory improvement in both study groups of 3xTg- AD mice as indicated by radial arm maze testing. As immunostaining showed a 58% reduction in hippocampal amyloid burden (p=0.009) in the group treated from 11 to 17 months and 48% reduction (p=0.003) in the group treated from 7 to 20 months compared to vehicle-treated Tg animals. Biochemical analyses and evaluation of the impact of our approach on tau related pathology are ongoing. In vitro results indicate that TLR9 activation enhances microglial uptake and degradation of aggregated As42. Whether TLR9 agonist can boost peripheral macrophages to clear As is being further explored in our studies using RAW 264.7 and differentiated human THP-1 macrophages cells. Conclusions: Immunomodulation targeting TLR9 signaling represents a novel immunotherapeutic approach for AD. The current results provide essential information prior to any clinical use of CpG ODN
— id: 136959, year: 2011, vol: 7, page: S665, stat: Journal Article,

Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome
Wegiel, Jerzy; Kaczmarski, Wojciech; Barua, Madhabi; Kuchna, Izabela; Nowicki, Krzysztof; Wang, Kuo-Chiang; Wegiel, Jarek; Yang, Shuang Ma; Frackowiak, Janusz; Mazur-Kolecka, Bozena; Silverman, Wayne P; Reisberg, Barry; Monteiro, Isabel; de Leon, Mony; Wisniewski, Thomas; Dalton, Arthur; Lai, Florence; Hwang, Yu-Wen; Adayev, Tatyana; Liu, Fei; Iqbal, Khalid; Iqbal, Inge-Grundke; Gong, Cheng-Xin
2011 Jan;70(1):36-50, Journal of neuropathology & experimental neurology
Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage-proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus, and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68 x of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R tau-positive NFTs in DS/AD subjects compared with that in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS
— id: 134289, year: 2011, vol: 70, page: 36, stat: Journal Article,

Specific anti-prp mucosal and systemic response in white tail deer vaccinated with attenuated salmonella expressing deer prp
Wisniewski T.; Mathiason C.; Wong V.; Hayes-Klug J.; Nalls A.; Anderson K.; Estevez V.; Yim L.; Brown D.; Chabalgoity J.A.; Hoover E.; Goni F.
2011 ;7(4 SUPPL 1):S687-S688, Alzheimer's & Dementia
Background: ChronicWasting Disease (CWD) is epidemic in deer and elk populations in parts of North American and poses a significant threat to humans. Although there has been no human transmission documented so far, CWD has been shown by two groups to be transmissible to squirrel monkeys. The CWD agent has been found in multiple biological fluids and tissues (including blood, muscle and feces) in both symptomatic and asymptomatic animals. It is highly infectious in the wild among deer and elk populations, with the likely major route of infection being oral. Previously, we were the first to show that scrapie prion infection via an oral route can be prevented in model wild-type CD-1 mice by vaccination using attenuated Salmonella expressing copies of murine PrP. Methods: We have performed oral inoculations in white tail deer, using attenuated salmonella expressing deer PrP. The animals were inoculated orally three times, and three additional boosts were performed which included tonsil and rectal inoculations with the inoculum supplemented with polymerized recombinant deer PrP. Control animals were inoculated with an attenuated salmonella not carrying any foreign protein. Results: Both groups of animals produced IgA anti-salmonella in plasma, saliva and feces. However, the vaccinated group had a low titer of anti-PrP IgG and IgA in plasma, as well as anti-PrP IgA in the saliva. Deer immunoglobulins were precipitated from plasma, saliva and feces; semi-purified and the heavy and light chains recognized in blots. The purified IgG and IgA from the plasma of a vaccinated animal reacted in Western blots strongly against polymerized PrP and salmonella antigens and to a lesser extent to monomers and dimers of mouse, sheep and deer recombinant PrP. Control deer showed a reaction only against the salmonella antigens in similar blots. Both groups were challenged with homogeneized CWD infected brains included in food bait. Conclusions: Our results show for the first time that a specific antibody response against the self-antigen PrP can be elicited in the biological fluids of large bovide mammals. We are expecting quantitative results of infection progression or protection, before the end of the year
— id: 136958, year: 2011, vol: 7, page: S687, stat: Journal Article,

Blocking the Apolipoprotein E/Amyloid-beta Interaction Reduces Fibrillar Vascular Amyloid Deposition and Cerebral Microhemorrhages in TgSwDI Mice
Yang, Jing; Ji, Yong; Mehta, Pankaj; Bates, Kristyn A; Sun, Yanjie; Wisniewski, Thomas
2011 Jan 1;24(2):269-285, Journal of Alzheimer's Disease
The accumulation of amyloid-beta (Abeta) peptides as toxic oligomers, amyloid plaques, and cerebral amyloid angiopathy (CAA) is critical in the pathogenesis of Alzheimer's disease (AD). The binding of Abeta peptides to apolipoprotein E (ApoE) plays an important role in modulation of amyloid deposition and clearance. We have shown that blocking the Abeta/ApoE interaction with Abeta12-28P, a nontoxic blood-brain-barrier permeable and non-fibrillogenic synthetic peptide, constitutes a novel therapeutic approach for AD by reducing Abeta parenchymal deposition. In the present study, we investigate this therapeutic effect on CAA in the transgenic (Tg) AD mice model (TgSwDI), which expresses Swedish (K670N/M671L), Dutch (E693Q)/Iowa (D694N) AbetaPP mutations. These mice develop abundant CAA beginning at the age of 6 months. Behavioral results show that A12-28P treated TgSwDI AD mice performed the same as wild-type mice, whereas vehicle treated TgSwDI were impaired in spatial memory. Furthermore, this treatment resulted in a significant reduction of total amyloid burden, especially the fibrillar vascular amyloid burden, which importantly was accompanied by a reduction in microhemorrhages and neuroinflammation. Measurement of Abeta levels in the brain homogenate revealed a significant decrease in both the total amount of Abeta and Abeta oligomer levels in A12-28P treated TgSwDI mice. These findings suggest that blocking the Abeta/ApoE interaction is a highly effective therapeutic approach for vascular amyloid deposition, in contrast to some other therapeutic approaches
— id: 130902, year: 2011, vol: 24, page: 269, stat: Journal Article,

Detection of amyloid plaques targeted by USPIO-Abeta1-42 in Alzheimer's disease transgenic mice using magnetic resonance microimaging
Yang, Jing; Zaim Wadghiri, Youssef; Minh Hoang, Dung; Tsui, Wai; Sun, Yanjie; Chung, Erika; Li, Yongsheng; Wang, Andrew; de Leon, Mony; Wisniewski, Thomas
2011 Apr 15;55(4):1600-1609, Neuroimage
Amyloid plaques are one of the pathological hallmarks of Alzheimer's disease (AD). The visualization of amyloid plaques in the brain is important to monitor AD progression and to evaluate the efficacy of therapeutic interventions. Our group has developed several contrast agents to detect amyloid plaques in vivo using magnetic resonance microimaging (muMRI) in AD transgenic mice, where we used intra-carotid mannitol to enhance blood-brain barrier (BBB) permeability. In the present study, we used ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with Abeta1-42 peptide to detect amyloid deposition along with mannitol for in vivo muMRI by femoral intravenous injection. A 3D gradient multi-echo sequence was used for imaging with a 100mum isotropic resolution. The amyloid plaques detected by T2*-weighted muMRI were confirmed with matched histological sections. Furthermore, two different quantitative analyses were used. The region of interest-based quantitative measurement of T2* values showed contrast-injected APP/PS1 mice had significantly reduced T2* values compared to wild-type mice. In addition, the scans were examined with voxel-based morphometry (VBM) using statistical parametric mapping (SPM) for comparison of contrast-injected AD transgenic and wild-type mice. The regional differences seen in VBM comparing USPIO-Abeta1-42 injected APP/PS1 and wild-type mice correlated with the amyloid plaque distribution histologically, contrasting with no differences between the two groups of mice without contrast agent injection in regions of the brain with amyloid deposition. Our results demonstrated that both approaches were able to identify the differences between AD transgenic mice and wild-type mice, after injected with USPIO-Abeta1-42. The feasibility of using less invasive intravenous femoral injections for amyloid plaque detection in AD transgenic mice facilitates using this method for longitudinal studies in the pathogenesis of AD
— id: 128789, year: 2011, vol: 55, page: 1600, stat: Journal Article,

Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an alzheimer's disease model mouse
Chung, Erika; Ji, Yong; Sun, Yanjie; Kascsak, Richard J; Kascsak, Regina B; Mehta, Pankaj D; Strittmatter, Stephen M; Wisniewski, Thomas
2010 ;11:130-130, BMC Neuroscience
ABSTRACT: BACKGROUND: Alzheimer's Disease (AD) is the most common of the conformational neurodegenerative disorders characterized by the conversion of a normal biological protein into a beta-sheet-rich pathological isoform. In AD the normal soluble Abeta (sAbeta) forms oligomers and fibrils which assemble into neuritic plaques. The most toxic form of Abeta is thought to be oligomeric. A recent study reveals the cellular prion protein, PrPC, to be a receptor for Abeta oligomers. Abeta oligomers suppress LTP signal in murine hippocampal slices but activity remains when pretreated with the PrP monoclonal anti-PrP antibody, 6D11. We hypothesized that targeting of PrPC to prevent Abeta oligomer-related cognitive deficits is a potentially novel therapeutic approach. APP/PS1 transgenic mice aged 8 months were intraperitoneally (i.p.) injected with 1 mg 6D11 for 5 days/week for 2 weeks. Two wild-type control groups were given either the same 6D11 injections or vehicle solution. Additional groups of APP/PS1 transgenic mice were given either i.p. injections of vehicle solution or the same dose of mouse IgG over the same period. The mice were then subjected to cognitive behavioral testing using a radial arm maze, over a period of 10 days. At the conclusion of behavioral testing, animals were sacrificed and brain tissue was analyzed biochemically or immunohistochemically for the levels of amyloid plaques, PrPC, synaptophysin, Abeta40/42 and Abeta oligomers. RESULTS: Behavioral testing showed a marked decrease in errors in 6D11 treated APP/PS1 Tg mice compared with the non-6D11 treated Tg groups (p < 0.0001). 6D11 treated APP/PS1 Tg mice behaved the same as wild-type controls indicating a recovery in cognitive learning, even after this short term 6D11 treatment. Brain tissue analysis from both treated and vehicle treated APP/PS1 groups indicate no significant differences in amyloid plaque burden, Abeta40/42, PrPC or Abeta oligomer levels. 6D11 treated APP/PS1 Tg mice had significantly greater synaptophysin immunoreactivity in the dentate gyrus molecular layer of the hippocampus compared to vehicle treated APP/PS1 Tg mice (p < 0.05). CONCLUSIONS: Even short term treatment with monoclonal antibodies such as 6D11 or other compounds which block the binding of Abeta oligomers to PrPC can be used to treat cognitive deficits in aged AD transgenic mice
— id: 114049, year: 2010, vol: 11, page: 130, stat: Journal Article,

Immunomodulation targeting abnormal protein conformation reduces pathology in a mouse model of Alzheimer's disease
Goni, Fernando; Prelli, Frances; Ji, Yong; Scholtzova, Henrieta; Yang, Jing; Sun, Yanjie; Liang, Feng-Xia; Kascsak, Regina; Kascsak, Richard; Mehta, Pankaj; Wisniewski, Thomas
2010 ;5(10):e13391-e13391, PLoS ONE
Many neurodegenerative diseases are characterized by the conformational change of normal self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high beta-sheet content and resistance to degradation. The most common is Alzheimer's disease (AD) where the normal soluble amyloid beta (sAbeta) peptide is converted into highly toxic oligomeric Abeta and fibrillar Abeta that deposits as neuritic plaques and congophilic angiopathy. Currently, there is no highly effective treatment for AD, but immunotherapy is emerging as a potential disease modifying intervention. A major problem with most active and passive immunization approaches for AD is that both the normal sAbeta and pathogenic forms are equally targeted with the potential of autoimmune inflammation. In order to avoid this pitfall, we have developed a novel immunomodulatory method that specifically targets the pathological conformations, by immunizing with polymerized British amyloidosis (pABri) related peptide which has no sequence homology to Abeta or other human proteins. We show that the pABri peptide through conformational mimicry induces a humoral immune response not only to the toxic Abeta in APP/PS1 AD transgenic mice but also to paired helical filaments as shown on AD human tissue samples. Treated APP/PS1 mice had a cognitive benefit compared to controls (p<0.0001), associated with a reduction in the amyloid burden (p = 0.0001) and Abeta40/42 levels, as well as reduced Abeta oligomer levels. This type of immunomodulation has the potential to be a universal beta-sheet disrupter, which could be useful for the prevention or treatment of a wide range of neurodegenerative diseases
— id: 114051, year: 2010, vol: 5, page: e13391, stat: Journal Article,

The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes
Wegiel, Jerzy; Kuchna, Izabela; Nowicki, Krzysztof; Imaki, Humi; Wegiel, Jarek; Marchi, Elaine; Ma, Shuang Yong; Chauhan, Abha; Chauhan, Ved; Bobrowicz, Teresa Wierzba; de Leon, Mony; Louis, Leslie A Saint; Cohen, Ira L; London, Eric; Brown, W Ted; Wisniewski, Thomas
2010 Jun;119(6):755-770, Acta neuropathologica
Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4-60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-mum-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype
— id: 119248, year: 2010, vol: 119, page: 755, stat: Journal Article,

Type, topography, and sequelae of neuropathological changes: Shaping clinical phenotype of autism
Wegiel, Jerzy; Wisniewski, Thomas; Chauhan, Abha; Chauhan, Ved; Kuchna, Izabela; Nowicki, Krzysztof; Imaki, Humi; Wegiel, Jarek; Ma, Shuang Yong; Bobrowicz, Teresa Wierzba; Cohen, Ira L; London, Eric; Brown, W. Ted
Autism: Oxidative stress, inflammation, and immune abnormalities Boca Raton, FL : CRC Press, 2010,
(from the chapter) The aim of this chapter is to identify the type, topography, and sequelae of neuropathological changes that contribute to the clinical phenotype of autism. Results of recent magnetic resonance imaging (MRI) and postmortem neuropathological and stereological studies of autism brain suggest a dynamic model of sequential subdivision of age- and brain-specific structural and functional changes. Acceleration of brain growth in the first year of life and deceleration in the second and third years appear to play a pivotal role in the onset of clinical signs of autism (Courchesne and Pierce, 2005b; Courchesne et al., 2001, 2003; Dawson et al., 2007; Dementieva et al., 2005; Gillberg and de Souza, 2002; Redcay and Courchesne, 2005). The range of deviation from the normal trajectory of brain growth may be a factor determining the severity of the disease (Courchesne et al., 2003). Developmental heterochronicity (differential rates of growth of various brain regions compared to controls), resulting in selective overgrowth of some brain regions, appears to be a key factor determining topography and brain regionspecific type of cytoarchitectonic changes (Carper and Courchesne, 2005; Carper et al., 2002; Courchesne et al., 2001; Hazlett et al., 2005; Sparks et al., 2002). Topographic developmental heterochronicity may result in impairment of both local and global connectivity, leading to local overconnectivity and impairment of long-distance connectivity (Baron-Cohen, 2004; Casanova et al., 2006; Courchesne and Pierce, 2005a). Stereological studies have revealed neuronal developmental heterochronicity in early childhood, resulting in selective developmental delay of the growth of neurons in some subcortical structures and the cerebellum during the most critical stage of development of social behaviors and communication skills (Wegiel et al., 2008). Distortions of brain and neuronal development are reflected in abnormal cortical minicolumn organization (Casanova et al., 2002,2006), local dysgenesis, and ectopias (Bauman and Kemper, 1985; Bauman et al., 1997; Kemper and Bauman, 1993,1998). These complex developmental abnormalities appear to lay the foundation for secondary and tertiary metabolic, structural, and functional changes, including seizures and risk of sudden unexpected death; signs of oxidative stress, early and enhanced accumulation of products of cell organelle degradation with lipofuscin deposition; modified processing of beta -amyloid precursor protein with accumulation of truncated amyloid beta; and other as of yet unidentified changes. Secondary pathologic changes appear to be indicators of the susceptibility of abnormally developing neurons to further modifications during cell maturation and aging. The pattern of morphological changes emerging from these multidisciplinary studies appears to represent a major trend. However, modifications of the course of disease and subpatterns of developmental changes result in a broad spectrum of morphological and clinical interindividual differences.
— id: 5288, year: 2010, vol: , page: 279, stat: Chapter,

Immunotherapeutic approaches for Alzheimer's disease in transgenic mouse models
Wisniewski, Thomas; Boutajangout, Allal
2010 Mar;214(2-3):201-218, Brain structure & function
Alzheimer's disease (AD) is a member of a category of neurodegenerative diseases characterized by the conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it resistant to degradation and neurotoxic. In the case of AD the normal soluble amyloid beta (sAbeta) peptide is converted into oligomeric/fibrillar Abeta. The oligomeric forms of Abeta are thought to be the most toxic, while fibrillar Abeta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is an essential part of the pathology. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror different aspects of AD pathology. Perhaps the most exciting of these approaches is immunomodulation. Vaccination is currently being tried for a range of age associated CNS disorders with great success being reported in many transgenic mouse models. However, there is a discrepancy between these results and current human clinical trials which highlights the limitations of current models and also uncertainties in our understanding of the underlying pathogenesis of AD. No current AD Tg mouse model exactly reflects all aspects of the human disease. Since the underlying etiology of sporadic AD is unknown, the process of creating better Tg models is in constant evolution. This is an essential goal since it will be necessary to develop therapeutic approaches which will be highly effective in humans
— id: 108917, year: 2010, vol: 214, page: 201, stat: Journal Article,

Vaccination as a therapeutic approach to Alzheimer's disease
Wisniewski, Thomas; Boutajangout, Allal
2010 Jan;77(1):17-31, Mount Sinai journal of medicine
Alzheimer's disease is the most common cause of dementia worldwide. Alzheimer's disease is a member of a broad range of neurodegenerative diseases characterized pathologically by the conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it neurotoxic. In the case of Alzheimer's disease, the normal soluble amyloid beta peptide is converted into oligomeric/fibrillar amyloid beta. The oligomeric forms of amyloid beta have been hypothesized to be the most toxic, whereas fibrillar amyloid beta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat Alzheimer's disease. Among the most exciting and advanced of these approaches is vaccination. Immunomodulation is being tried for a range of neurodegenerative disorders, with great success being reported in most model animal trials; however, the much more limited human data have shown more modest clinical success so far, with encephalitis occurring in a minority of patients treated with active immunization. The immunomodulatory approaches for neurodegenerative diseases involve targeting a self-protein, albeit in an abnormal conformation; hence, effective enhanced clearance of the disease-associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation within the central nervous system. The design of future immunomodulatory approaches that are more focused is dependent on addressing a number of questions, including when is the best time to start immunization, what are the most appropriate targets for vaccination, and is amyloid central to the pathogenesis of Alzheimer's disease or is it critical to target tau-related pathology also. In this review, we discuss the past experience with vaccination for Alzheimer's disease and the development of possible future strategies that target both amyloid beta-related and tau-related pathologies. Mt Sinai J Med 77:17&-31, 2010. (c) 2010 Mount Sinai School of Medicine
— id: 106502, year: 2010, vol: 77, page: 17, stat: Journal Article,

Immunomodulation for prion and prion-related diseases
Wisniewski, Thomas; Goni, Fernando
2010 Dec;9(12):1441-1452, Expert review of vaccines
Prion diseases are a unique category of illness, affecting both animals and humans, where the underlying pathogenesis is related to a conformational change of a normal self protein called cellular prion protein to a pathological and infectious conformer known as scrapie prion protein (PrP(Sc)). Currently, all prion diseases lack effective treatment and are universally fatal. Past experiences with bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease mainly in Europe, as well as the current epidemic of chronic wasting disease in North America, have highlighted the need to develop prophylactic and/or therapeutic approaches. In Alzheimer's disease that, like prion disease, is a conformational neurodegenerative disorder, both passive and active immunization has been shown to be highly effective in model animals at preventing disease and cognitive deficits, with emerging data from human trials suggesting that this approach is able to reduce amyloid-related pathology. However, any immunomodulatory approach aimed at a self-antigen has to finely balance an effective humoral immune response with potential autoimmune toxicity. The prion diseases most commonly acquired by infection typically have the alimentary tract as a portal of infectious agent entry. This makes mucosal immunization a potentially attractive method to produce a local immune response that partially or completely prevents prion entry across the gut barrier, while at the same time producing modulated systemic immunity that is unlikely to be associated with toxicity. Our results using an attenuated Salmonella vaccine strain expressing the prion protein showed that mucosal vaccination can protect against prion infection from a peripheral source, suggesting the feasibility of this approach. It is also possible to develop active and/or passive immunomodulatory approaches that more specifically target PrP(Sc) or target the shared pathological conformer found in numerous conformational disorders. Such approaches could have a significant impact on many of the common age-associated dementias
— id: 114848, year: 2010, vol: 9, page: 1441, stat: Journal Article,

Murine models of Alzheimer's disease and their use in developing immunotherapies
Wisniewski, Thomas; Sigurdsson, Einar M
2010 Oct;1802(10):847-859, Biochimica & biophysica acta
Alzheimer's disease (AD) is one of the categories of neurodegenerative diseases characterized by a conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it resistant to degradation and neurotoxic. In AD, the normal soluble amyloid beta (sAbeta) peptide is converted into oligomeric/fibrillar Abeta. The oligomeric forms of Abeta are thought to be the most toxic, while fibrillar Abeta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. An additional important feature of AD is the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror specific aspects of AD pathology. None of the current murine models is a perfect match of the human disease. Perhaps the most exciting of the therapeutic approaches being developed is immunomodulation targeting the aggregating proteins, Abeta and tau. This type of AD therapy is currently being assessed in many transgenic mouse models, and promising findings have led to clinical trials. However, there is a discrepancy between results in murine models and ongoing clinical trials, which highlight the limitations of these models and also of our understanding of the underlying etiology and pathogenesis of AD. Because of these uncertainties, Tg models for AD are continuously being refined with the aim to better understand the disease and to enhance the predictive validity of potential treatments such as immunotherapies
— id: 112199, year: 2010, vol: 1802, page: 847, stat: Journal Article,

Dissolution of arterial platelet thrombi in vivo with a bifunctional platelet GPIIIa49-66 ligand which specifically targets the platelet thrombus
Zhang, Wei; Li, Yong-Sheng; Nardi, Michael A; Dang, Suying; Yang, Jing; Ji, Yong; Li, Zongdong; Karpatkin, Simon; Wisniewski, Thomas
2010 Sep 30;116(13):2336-2344, Blood
Patients with HIV-1 immune-related thrombocytopenia have a unique antibody (Ab) against integrin GPIIIa49-66 capable of inducing oxidative platelet fragmentation via Ab activation of platelet nicotinamide adenine dinucleotide phosphate oxidase and 12-lipoxygenase releasing reactive oxygen species. Using a phage display single-chain antibody (scFv) library, we developed a novel human monoclonal scFv Ab against GPIIIa49-66 (named A11) capable of inducing fragmentation of activated platelets. In this study, we investigated the in vivo use of A11. We show that A11 does not induce significant thrombocytopenia or inhibit platelet function. A11 can prevent the cessation of carotid artery flow produced by induced artery injury and dissolve the induced thrombus 2 hours after cessation of blood flow. In addition, A11 can prevent, as well as ameliorate, murine middle cerebral artery stroke, without thrombocytopenia or brain hemorrhage. To further optimize the antithrombotic activity of A11, we produced a bifunctional A11-plasminogen first kringle agent (SLK), which homes to newly deposited fibrin strands within and surrounding the platelet thrombus, reducing effects on nonactivated circulating platelets. Indeed, SLK is able to completely reopen occluded carotid vessels 4 hours after cessation of blood flow, whereas A11 had no effect at 4 hours. Thus, a new antithrombotic agent was developed for platelet thrombus clearance
— id: 114164, year: 2010, vol: 116, page: 2336, stat: Journal Article,

Memantine Lowers beta-Amyloid Levels and Improves Cognitive Performance: Evidence from Preclinical Studies
Banerjee, P; Lahiri, DK; Tanila, H; Wisniewski, T; LaFerla, F
2009 APR 15 ;65(8):65S-65S, Biological psychiatry
— id: 97976, year: 2009, vol: 65, page: 65S, 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,

FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease
Mosconi, Lisa; Mistur, Rachel; Switalski, Remigiusz; Tsui, Wai Hon; Glodzik, Lidia; Li, Yi; Pirraglia, Elizabeth; De Santi, Susan; Reisberg, Barry; Wisniewski, Thomas; de Leon, Mony J
2009 May;36(5):811-822, European journal of nuclear medicine & molecular imaging
PURPOSE: We report the first clinicopathological series of longitudinal FDG-PET scans in post-mortem (PM) verified cognitively normal elderly (NL) followed to the onset of Alzheimer's-type dementia (DAT), and in patients with mild DAT with progressive cognitive deterioration. METHODS: Four NL subjects and three patients with mild DAT received longitudinal clinical, neuropsychological and dynamic FDG-PET examinations with arterial input functions. NL subjects were followed for 13 +/- 5 years, received FDG-PET examinations over 7 +/- 2 years, and autopsy 6 +/- 3 years after the last FDG-PET. Two NL declined to mild cognitive impairment (MCI), and two developed probable DAT before death. DAT patients were followed for 9 +/- 3 years, received FDG-PET examinations over 3 +/- 2 years, and autopsy 7 +/- 1 years after the last FDG-PET. Two DAT patients progressed to moderate-to-severe dementia and one developed vascular dementia. RESULTS: The two NL subjects who declined to DAT received a PM diagnosis of definite AD. Their FDG-PET scans indicated a progression of deficits in the cerebral metabolic rate for glucose (CMRglc) from the hippocampus to the parietotemporal and posterior cingulate cortices. One DAT patient showed AD with diffuse Lewy body disease (LBD) at PM, and her last in vivo PET was indicative of possible LBD for the presence of occipital as well as parietotemporal hypometabolism. CONCLUSION: Progressive CMRglc reductions on FDG-PET occur years in advance of clinical DAT symptoms in patients with pathologically verified disease. The FDG-PET profiles in life were consistent with the PM diagnosis
— id: 91500, year: 2009, vol: 36, page: 811, stat: Journal Article,

Anti-PrP Mab 6D11 suppresses PrP(Sc) replication in prion infected myeloid precursor line FDC-P1/22L and in the lymphoreticular system in vivo
Sadowski, Martin J; Pankiewicz, Joanna; Prelli, Frances; Scholtzova, Henrieta; Spinner, Daryl S; Kascsak, Regina B; Kascsak, Richard J; Wisniewski, Thomas
2009 May;34(2):267-278, Neurobiology of disease
The pathogenesis of prion diseases is related to conformational transformation of cellular prion protein (PrP(C)) into a toxic, infectious, and self-replicating conformer termed PrP(Sc). Following extracerebral inoculation, the replication of PrP(Sc) is confined for months to years to the lymporeticular system (LRS) before the secondary CNS involvement results in occurrence of neurological symptoms. Therefore, replication of PrP(Sc), in the early stage of infection can be targeted by therapeutic approaches, which like passive immunization have limited blood-brain-barrier penetration. In this study, we show that 6D11 anti-PrP monoclonal antibody (Mab) prevents infection on a FDC-P1 myeloid precursor cell line stably infected with 22L mouse adapted scrapie strain. Passive immunization of extracerebrally infected CD-1 mice with Mab 6D11 resulted in effective suppression of PrP(Sc) replication in the LRS. Although, a rebound of PrP(Sc) presence occurred when the Mab 6D11 treatment was stopped, passively immunized mice showed a prolongation of the incubation period by 36.9% (pb0.0001) and a significant decrease in CNS pathology compared to control groups receiving vehicle or murine IgG. Our results indicate that antibody-based therapeutic strategies can be used, even on a short-term basis, to delay or prevent disease in subjects accidentally exposed to prions
— id: 101114, year: 2009, vol: 34, page: 267, stat: Journal Article,

Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology
Scholtzova, Henrieta; Kascsak, Richard J; Bates, Kristyn A; Boutajangout, Allal; Kerr, Daniel J; Meeker, Harry C; Mehta, Pankaj D; Spinner, Daryl S; Wisniewski, Thomas
2009 Feb 11;29(6):1846-1854, Journal of neuroscience
The pathogenesis of Alzheimer's disease (AD) is thought to be related to the accumulation of amyloid beta (Abeta) in amyloid deposits and toxic oligomeric species. Immunomodulation is emerging as an effective means of shifting the equilibrium from Abeta accumulation to clearance; however, excessive cell mediated inflammation and cerebral microhemorrhages are two forms of toxicity which can occur with this approach. Vaccination studies have so far mainly targeted the adaptive immune system. In the present study, we have stimulated the innate immune system via the Toll-like receptor 9 (TLR9) with cytosine-guanosine-containing DNA oligodeoxynucleotides in Tg2576 AD model transgenic mice. This treatment produced a 66% and 80% reduction in the cortical (p = 0.0001) and vascular (p = 0.0039) amyloid burden, respectively, compared with nontreated AD mice. This was in association with significant reductions in Abeta42, Abeta40, and Abeta oligomer levels. We also show that treated Tg mice performed similarly to wild-type mice on a radial arm maze. Our data suggest that stimulation of innate immunity via TLR9 is highly effective at reducing the parenchymal and vascular amyloid burden, along with Abeta oligomers, without apparent toxicity
— id: 92200, year: 2009, vol: 29, page: 1846, 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,

AD vaccines: conclusions and future directions
Wisniewski, Thomas
2009 Apr;8(2):160-166, CNS & neurological disorders drug targets
— id: 100596, year: 2009, vol: 8, page: 160, stat: Journal Article,

An entorhinal cortex sulcal pattern is associated with Alzheimer's disease
Zhan, Jiong; Brys, Miroslaw; Glodzik, Lidia; Tsui, Wai; Javier, Elizabeth; Wegiel, Jerzy; Kuchna, Izabela; Pirraglia, Elizabeth; Li, Yi; Mosconi, Lisa; Saint Louis, Leslie A; Switalski, Remigiusz; De Santi, Susan; Kim, Byeong C; Wisniewski, Thomas; Reisberg, Barry; Bobinski, Matthew; de Leon, Mony J
2009 Mar;30(3):874-882, Human brain mapping
OBJECTIVES:: Magnetic resonance (MRI) studies rely on sulcal boundaries to delineate the human entorhinal cortex (EC) and typically show that EC size is reduced in Alzheimer's disease (AD) and a predictor of future dementia. However, it is unknown if variations in the EC sulcal patterns are associated with AD. We classified the lateral EC sulcal boundary as either a rhinal or collateral pattern and tested the hypotheses that the rhinal pattern was (1) more common in AD and (2) associated with a smaller EC size. EXPERIMENTAL DESIGN:: MRI was used to determine the prevalence of the rhinal and collateral EC patterns in 421 subjects (212 AD, 107 old normal (ONL), and 102 young NL (YNL). Anatomical validation studies of normal subjects were conducted at postmortem in 34 brain hemispheres and in vivo with 21 MRI volume studies. EC pattern reliability was studied with MRI in both cross-sectional and longitudinal designs. PRINCIPAL OBSERVATIONS:: The rhinal pattern was more frequent in the right hemisphere in AD (47%) compared with ONL (28%, odds ratio = 2.25, P = 0.001). EC pattern was not related to ApoE genotype. The validations showed that the EC sulcal pattern was not associated with the neuronal number, surface area, or volume of the EC. In patients with antemortem MRI studied at postmortem it was equivalently determined, that EC patterns are reliably determined on MRI and do not change with the progressive atrophy of AD. CONCLUSIONS:: The data indicate that the right hemisphere rhinal pattern is over represented in AD as compared with control. However, in normal subjects the EC rhinal pattern is not associated with a diminished EC tissue size. It remains to be demonstrated if the right EC rhinal sulcus pattern association with AD reflects genetic or developmental influences. Hum Brain Mapp, 2008. (c) 2008 Wiley-Liss, Inc
— id: 76758, year: 2009, vol: 30, page: 874, stat: Journal Article,

Enhanced accumulation of AB neurons in autism
Brown, WT; Kuchna, I; Nowicki, K; Wegiel, J; Wisniewski, T; Wegiel, J
2008 ;52(3):659-659, Journal of intellectual disability research : JIDR
— id: 97623, year: 2008, vol: 52, page: 659, stat: Journal Article,

Prominent Neuroleptic Sensitivity in a Case of Early-onset Alzheimer Disease due to Presenilin-1 G206A Mutation
Cercy, Steven P; Sadowski, Martin J; Wisniewski, Thomas
2008 Sep;21(3):190-195, Cognitive & behavioral neurology
OBJECTIVE: We describe atypical motor and cognitive features in a case of familial Alzheimer disease (FAD) due to presenilin-1 (PS-1) mutation. BACKGROUND: Extrapyramidal signs (EPS) typically are a late-presenting feature of sporadic Alzheimer disease (AD), but relatively little data are available regarding EPS in FAD. METHOD: A 59-year-old, right-handed man of Caribbean-Hispanic descent underwent brain imaging studies, laboratory tests for AD, and serial neurologic and neuropsychologic evaluations. RESULTS: The patient presented with recent-onset delusional ideation associated with cognitive decline. Prominent EPS developed soon after initiation of an atypical neuroleptic agent. Neuropsychologic evaluation revealed global cognitive deficits; he was found to be a carrier of a PS-1 point mutation at position G206A. EPS resolved completely after discontinuing the neuroleptic agent and coincided with improved motor speed, set initiation, and verbal fluency. CONCLUSIONS: Severe neuroleptic sensitivity and associated deficits of cognitive speed occurred in response to a dopaminergic antagonist agent; both responded readily to withdrawal of the offending agent. Patients with PS-1 AD may be at substantially increased risk of neuroleptic-induced EPS. That feature underscores the heterogeneity of the FAD clinical phenotype
— id: 83107, year: 2008, vol: 21, page: 190, stat: Journal Article,

5-Lipoxygenase gene disruption reduces amyloid-beta pathology in a mouse model of Alzheimer's disease
Firuzi, Omidreza; Zhuo, Jiamin; Chinnici, Cinzia M; Wisniewski, Thomas; Pratico, Domenico
2008 Apr;22(4):1169-1178, FASEB journal
5-Lipoxygenase (5LO), by producing leukotrienes, is a proinflammatory enzyme, and there is evidence suggesting that it is up-regulated with aging and may be involved in Alzheimer's disease (AD). In this paper, we studied the effect of 5LO-targeted gene disruption on the amyloid phenotype of a transgenic mouse model of AD, the Tg2576. Amyloid-beta (Abeta) deposition in the brains of Tg2576 mice lacking 5LO was reduced by 64-80% compared with Tg2576 controls. This reduction was associated with a similar significant decrease in Abeta levels measured by sandwich ELISA. Absence of 5LO did not induce any significant change in amyloid-beta precursor protein (APP) levels and processing, or Abeta catabolic pathways. Furthermore, in vitro studies showed that 5LO activation or 5LO metabolites increase, whereas 5LO inhibition decreases, Abeta formation, secondary to correspondent changes in gamma-secretase activity. These data establish for the first time a novel functional role for 5LO in the pathogenesis of AD-like amyloidosis, thereby modulating gamma-secretase activity. Our work suggests that pharmacological inhibition of 5LO could provide a novel therapeutic tool for AD
— id: 135343, year: 2008, vol: 22, page: 1169, 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
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,

A novel human disease with abnormal prion protein sensitive to protease
Gambetti, Pierluigi; Dong, Zhiqian; Yuan, Jue; Xiao, Xiangzhu; Zheng, Mengjie; Alshekhlee, Amer; Castellani, Rudy; Cohen, Mark; Barria, Marcelo A; Gonzalez-Romero, D; Belay, Ermias D; Schonberger, Lawrence B; Marder, Karen; Harris, Carrie; Burke, James R; Montine, Thomas; Wisniewski, Thomas; Dickson, Dennis W; Soto, Claudio; Hulette, Christine M; Mastrianni, James A; Kong, Qingzhong; Zou, Wen-Quan
2008 Jun;63(6):697-708, Annals of neurology
OBJECTIVE: To report a novel prion disease characterized by distinct histopathological and immunostaining features, and associated with an abnormal isoform of the prion protein (PrP) that, contrary to the common prion diseases, is predominantly sensitive to protease digestion. METHODS: Eleven subjects were investigated at the National Prion Disease Pathology Surveillance Center for clinical, histopathological, immunohistochemical, genotypical, and PrP characteristics. RESULTS: Patients presented with behavioral and psychiatric manifestations on average at 62 years, whereas mean disease duration was 20 months. The type of spongiform degeneration, the PrP immunostaining pattern, and the presence of microplaques distinguished these cases from those with known prion diseases. Typical protease-resistant PrP was undetectable in the cerebral neocortex with standard diagnostic procedures. After enrichment, abnormal PrP was detected at concentrations 16 times lower than common prion diseases; it included nearly 4 times less protease-resistant PrP, which formed a distinct electrophoretic profile. The subjects examined comprised about 3% of sporadic cases evaluated by the National Prion Disease Pathology Surveillance Center. Although several subjects had family histories of dementia, no mutations were found in the PrP gene open reading frame. INTERPRETATION: The distinct histopathological, PrP immunohistochemical, and physicochemical features, together with the homogeneous genotype, indicate that this is a previously unidentified type of disease involving the PrP, which we designated 'protease-sensitive prionopathy' (or PSPr). Protease-sensitive prionopathy is not rare among prion diseases, and it may be even more prevalent than our data indicate because protease-sensitive prionopathy cases are likely also to be classified within the group of non-Alzheimer's dementias
— id: 79464, year: 2008, vol: 63, page: 697, stat: Journal Article,

High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice
Goni, F; Prelli, F; Schreiber, F; Scholtzova, H; Chung, E; Kascsak, R; Brown, D R; Sigurdsson, E M; Chabalgoity, J A; Wisniewski, T
2008 May 15;153(3):679-686, Neuroscience
Significant outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP(C) (C for cellular), to a toxic and infectious form, PrP(Sc) (Sc for scrapie). None of the prionoses currently have an effective treatment. Some forms of prion disease are thought to be spread by oral ingestion of PrP(Sc), such as chronic wasting disease and variant Creutzfeldt-Jakob disease. Attempts to obtain an active immunization in wild-type animals have been hampered by auto-tolerance to PrP and potential toxicity. Previously, we demonstrated that it is possible to overcome tolerance and obtain a specific anti-PrP antibody response by oral inoculation of the PrP protein expressed in an attenuated Salmonella vector. This past study showed that 30% of vaccinated animals were free of disease more than 350 days post-challenge. In the current study we have both optimized the vaccination protocol and divided the vaccinated mice into low and high immune responder groups prior to oral challenge with PrP(Sc) scrapie strain 139A. These methodological refinements led to a significantly improved therapeutic response. 100% of mice with a high mucosal anti-PrP titer immunoglobulin (Ig) A and a high systemic IgG titer, prior to challenge, remained without symptoms of PrP infection at 400 days (log-rank test P<0.0001 versus sham controls). The brains from these surviving clinically asymptomatic mice were free of PrP(Sc) infection by Western blot and histological examination. These promising findings suggest that effective mucosal vaccination is a feasible and useful method for overcoming tolerance to PrP and preventing prion infection via an oral route
— id: 99013, year: 2008, vol: 153, page: 679, stat: Journal Article,

Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization
Klyubin, Igor; Betts, Vicki; Welzel, Alfred T; Blennow, Kaj; Zetterberg, Henrik; Wallin, Anders; Lemere, Cynthia A; Cullen, William K; Peng, Ying; Wisniewski, Thomas; Selkoe, Dennis J; Anwyl, Roger; Walsh, Dominic M; Rowan, Michael J
2008 Apr 16;28(16):4231-4237, Journal of neuroscience
The current development of immunotherapy for Alzheimer's disease is based on the assumption that human-derived amyloid beta protein (Abeta) can be targeted in a similar manner to animal cell-derived or synthetic Abeta. Because the structure of Abeta depends on its source and the presence of cofactors, it is of great interest to determine whether human-derived oligomeric Abeta species impair brain function and, if so, whether or not their disruptive effects can be prevented using antibodies. We report that untreated ex vivo human CSF that contains Abeta dimers rapidly inhibits hippocampal long-term potentiation in vivo and that acute systemic infusion of an anti-Abeta monoclonal antibody can prevent this disruption of synaptic plasticity. Abeta monomer isolated from human CSF did not affect long-term potentiation. These results strongly support a strategy of passive immunization against soluble Abeta oligomers in early Alzheimer's disease
— id: 78679, year: 2008, vol: 28, page: 4231, stat: Journal Article,

Prion Diseases
Sadowski M; Verma A; Wisniewski T
Neurology in clinical practice Philadelphia, PA : Butterworth-Heinemann/Elsevier, 2008,
— id: 4960, year: 2008, vol: , page: 1567, stat: Chapter,

Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's-disease-model transgenic mice shown as by micromagnetic resonance imaging
Scholtzova, Henrieta; Wadghiri, Youssef Z; Douadi, Moustafa; Sigurdsson, Einar M; Li, Yong-Sheng; Quartermain, David; Banerjee, Pradeep; Wisniewski, Thomas
2008 Sep;86(12):2784-2791, Journal of neuroscience research
Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to improve learning and memory in several preclinical models of Alzheimer's disease (AD). Memantine has also been shown to reduce the levels of amyloid beta (Abeta) peptides in human neuroblastoma cells as well as to inhibit Abeta oligomer-induced synaptic loss. In this study, we assessed whether NMDA receptor inhibition by memantine in transgenic mice expressing human amyloid-beta precursor protein (APP) and presenilin 1 (PS1) is associated with cognitive benefit and amyloid burden reduction by using object recognition, micromagnetic resonance imaging (muMRI), and histology. APP/PS1 Tg mice were treated either with memantine or with vehicle for a period of 4 months starting at 3 months of age. After treatment, the mice were subjected to an object recognition test and analyzed by ex vivo muMRI, and histological examination of amyloid burden. muMRI was performed following injection with gadolinium-DTPA-Abeta(1-40). We found that memantine-treated Tg mice performed the same as wild-type control mice, whereas the performance of vehicle-treated Tg mice was significantly impaired (P = 0.0081, one-way ANOVA). Compared with vehicle-treated animals, memantine-treated Tg mice had a reduced plaque burden, as determined both histologically and by muMRI. This reduction in amyloid burden correlates with an improvement in cognitive performance. Thus, our findings provide further evidence of the potential role of NMDA receptor antagonists in ameliorating AD-related pathology. In addition, our study shows, for the first time, the utility of muMRI in conjunction with gadolinium-labeled Abeta labeling agents to monitor the therapeutic response to amyloid-reducing agents. (c) 2008 Wiley-Liss, Inc
— id: 79463, year: 2008, vol: 86, page: 2784, stat: Journal Article,

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice
Sigurdsson, Einar M; Wadghiri, Youssef Z; Mosconi, Lisa; Blind, Jeffrey A; Knudsen, Elin; Asuni, Ayodeji; Scholtzova, Henrieta; Tsui, Wai H; Li, Yongsheng; Sadowski, Martin; Turnbull, Daniel H; de Leon, Mony J; Wisniewski, Thomas
2008 Jun;29(6):836-847, Neurobiology of aging
Amyloid plaques are a characteristic feature in Alzheimer's disease (AD). A novel non-toxic contrast agent is presented, Gd-DTPA-K6Abeta1-30, which is homologous to Abeta, and allows plaque detection in vivo. muMRI was performed on AD model mice and controls prior to and following intracarotid injection with Gd-DTPA-K6Abeta1-30 in mannitol solution, to transiently open the blood-brain barrier. A gradient echo T2(*)-weighted sequence was used to provide 100mum isotropic resolution with imaging times of 115min. The scans were examined with voxel-based analysis (VBA) using statistical parametric mapping, for un-biased quantitative comparison of ligand-injected mice and controls. The results indicate that: (1) Gd-DTPA-K6Abeta1-30 is an effective, non-toxic, ligand for plaque detection when combined with VBA (p</=0.01-0.001), comparing pre and post-ligand injection scans. (2) Large plaques can be detected without the use of a contrast agent and this detection co-localizes with iron deposition. (3) Smaller, earlier plaques require contrast ligand for MRI visualization. Our ligand when combined with VBA may be useful for following therapeutic approaches targeting amyloid in transgenic mouse models
— id: 71031, year: 2008, vol: 29, page: 836, stat: Journal Article,

Accelerated prion disease pathogenesis in Toll-like receptor 4 (TLR4) signaling-mutant mice
Spinner, Daryl S; Cho, In Soo; Park, Seung Yong; Kim, Jae Il; Meeker, Harry C; Ye, Xuemin; Lafauci, Giuseppe; Kerr, Daniel J; Flory, Michael J; Kim, Bo Sook; Kascsak, Regina B; Wisniewski, Thomas; Levis, William R; Schuller-Levis, Georgia B; Carp, Richard I; Park, Eunkyue; Kascsak, Richard J
2008 Nov;82(21):10701-10708, Journal of virology
Prion diseases such as scrapie involve the accumulation of disease-specific prion protein, PrP(Sc), in the brain. Toll-like receptors (TLRs) are a family of proteins that recognize microbial constituents and are central players in host innate immune response. The TLR9 agonist unmethylated CpG DNA was shown to prolong the scrapie incubation period in mice, suggesting that innate immune activation interferes with prion disease progression. Thus it was predicted that ablation of TLR signaling would result in accelerated pathogenesis. C3H/HeJ (Tlr4(Lps-d)) mice, which possess a mutation in the TLR4 intracellular domain preventing TLR4 signaling, and strain-matched wild-type control (C3H/HeOuJ) mice were infected intracerebrally or intraperitoneally with various doses of scrapie inoculum. Incubation periods were significantly shortened in C3H/HeJ compared with C3H/HeOuJ mice, regardless of the route of infection or dose administered. At the clinical phase of disease, brain PrP(Sc) levels in the two strains of mice showed no significant differences by Western blot. In addition, compared with macrophages from C3H/HeOuJ mice, those from C3H/HeJ mice were unresponsive to fibrillogenic PrP peptides (PrP106-126 and PrP118-135) and the TLR4 agonist lipopolysaccharide, but not to the TLR2 agonist zymosan, as measured by cytokine production. These data confirm that innate immune activation via TLR signaling interferes with scrapie infection. Furthermore, the results also suggest that the scrapie pathogen, or a component(s) thereof, is capable of stimulating an innate immune response that is active in the central nervous system, since C3H/HeJ mice, which lack the response, exhibit shortened incubation periods following both intraperitoneal and intracerebral infections
— id: 83108, year: 2008, vol: 82, page: 10701, stat: Journal Article,

The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome
Wegiel, Jerzy; Dowjat, Karol; Kaczmarski, Wojciech; Kuchna, Izabela; Nowicki, Krzysztof; Frackowiak, Janusz; Mazur Kolecka, Bozena; Wegiel, Jarek; Silverman, Wayne P; Reisberg, Barry; Deleon, Mony; Wisniewski, Thomas; Gong, Cheng-Xin; Liu, Fei; Adayev, Tatyana; Chen-Hwang, Mo-Chou; Hwang, Yu-Wen
2008 Oct;116(4):391-407, Acta neuropathologica
The gene encoding the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A (DYRK1A) is located in the Down syndrome (DS) critical region of chromosome 21. The third copy of DYRK1A is believed to contribute to abnormal brain development in patients with DS. In vitro studies showing that DYRK1A phosphorylates tau protein suggest that this kinase is also involved in tau protein phosphorylation in the human brain and contributes to neurofibrillary degeneration, and that this contribution might be enhanced in patients with DS. To explore this hypothesis, the brain tissue from 57 subjects including 16 control subjects, 21 patients with DS, and 20 patients with sporadic Alzheimer's disease (AD) was examined with two antibodies to the amino-terminus of DYRK1A (7F3 and G-19), as well as two polyclonal antibodies to its carboxy-terminus (X1079 and 324446). Western blots demonstrated higher levels of full-length DYRK1A in the brains of patients with DS when compared to control brains. Immunocytochemistry revealed that DYRK1A accumulates in neurofibrillary tangles (NFTs) in subjects with sporadic AD and in subjects with DS/AD. Overexpression of DYRK1A in patients with DS was associated with an increase in DYRK1A-positive NFTs in a gene dosage-dependent manner. Results support the hypothesis that overexpressed DYRK1A contributes to neurofibrillary degeneration in DS more significantly than in subjects with two copies of the DYRK1A gene and sporadic AD. Immunoreactivity with antibodies against DYRK1A not only in NFTs but also in granules in granulovacuolar degeneration and in corpora amylacea suggests that DYRK1A is involved in all three forms of degeneration and that overexpression of this kinase may contribute to the early onset of these pathologies in DS
— id: 80400, year: 2008, vol: 116, page: 391, stat: Journal Article,

Amyloid-beta immunisation for Alzheimer's disease
Wisniewski, Thomas; Konietzko, Uwe
2008 Sep;7(9):805-811, Lancet neurology
Alzheimer's disease is the main cause of dementia in elderly people and is becoming an ever greater problem as societies worldwide age. Treatments that stop or at least effectively modify disease course do not yet exist. In Alzheimer's disease, the conversion of the amyloid-beta peptide (Abeta) from a physiological water-soluble monomeric form into neurotoxic oligomeric and fibrillar forms rich in stable beta-sheet conformations is an important event. The most toxic forms of Abeta are thought to be oligomers, and dimers might be the smallest neurotoxic species. Numerous immunological approaches that prevent the conversion of the normal precursor protein into pathological forms or that accelerate clearance are in development. More than ten new approaches to active and passive immunotherapy are under investigation in clinical trials with the aim of producing safe methods for immunological therapy and prevention. A delicate balance between immunological clearance of an endogenous protein with acquired toxic properties and the induction of an autoimmune reaction must be found
— id: 81584, year: 2008, vol: 7, page: 805, stat: Journal Article,

Preventing beta-amyloid fibrillization and deposition: beta-sheet breakers and pathological chaperone inhibitors
Wisniewski, Thomas; Sadowski, Martin
2008 ;9 Suppl 2:S5-S5, BMC Neuroscience
Central to the pathogenesis of Alzheimer's disease (AD) is the conversion of normal, soluble beta-amyloid (sAbeta) to oligomeric, fibrillar Abeta. This process of conformational conversion can be influenced by interactions with other proteins that can stabilize the disease-associated state; these proteins have been termed 'pathological chaperones'. In a number of AD models, intervention that block soluble Abeta aggregation, including beta-sheet breakers, and compounds that block interactions with pathological chaperones, have been shown to be highly effective. When combined with early pathology detection, these therapeutic strategies hold great promise as effective and relatively toxicity free methods of preventing AD related pathology
— id: 91501, year: 2008, vol: 9 Suppl 2, page: S5, stat: Journal Article,

A blood test for prion: disease associated prion aggregate is detected in the blood of infected but asymptomatic animals
Chang, Binggong; Cheng, Xin; Yin, Shaoman; Pan, Tao; Zhang, Hongtao; Wong, Poki; Kang, Shin-Chung; Xiao, Fan; Yan, Huimin; Li, Chaoyang; Wolfe, Lisa L; Miller, Michael W; Wisniewski, Thomas; Greene, Mark I; Sy, Man-Sun
2007 Jan;14(1):36-43, Clinical & vaccine immunology
We have developed a sensitive in vitro assay for detecting disease associated prion aggregates by combining an aggregation specific enzyme-linked immunosorbent assay (AS-ELISA) with a Fluorescent Amplification Catalyzed by T7 RNA polymerase Technique (FACTT). The new assay, named AS-FACTT, is much more sensitive than AS-ELISA and could detect prion aggregates in the brain of mice as early as 7 days after an intra-peritoneal inoculation of PrP(Sc). However, AS-FACTT was still unable to detect prion aggregates in blood of infected mice. To further improve the detection limit of AS-FACTT, we added an additional prion amplification step (Am) and developed a third generation assay, termed Am-A-FACTT. Am-A-FACTT has 100% sensitivity and specificity in detecting disease-associated prion aggregates in blood of infected mice at late but still asymptomatic stages of disease. At a very early stage, Am-A-FACTT had a sensitivity of 50% and specificity of 100%. Most importantly, Am-A-FACTT also detects prion aggregates in blood of mule deer infected with a naturally occurring prion disease, chronic wasting disease. Application of this assay to cattle, sheep, and humans could safeguard food supplies and prevent human contagion
— id: 69182, year: 2007, vol: 14, page: 36, stat: Journal Article,

Styryl-Based Compounds as Potential in vivo Imaging Agents for beta-Amyloid Plaques
Li, Qian; Min, Jaeki; Ahn, Young-Hoon; Namm, Joshua; Kim, Eun Min; Lui, Rowena; Kim, Hye Yun; Ji, Yong; Wu, Hueizhi; Wisniewski, Thomas; Chang, Young-Tae
2007 Aug 20;8(14):1679-1687, Chembiochem : a European journal of chemical biology
A group of styryl-based neutral compounds has been synthesized in this study for potential use as in vivo imaging agents for beta-amyloid plaques. Of 56 candidates, 14 compounds were found to label beta-amyloid plaques well on Alzheimer's disease (AD) human brain sections in vitro. The binding affinity to beta-amyloid fibrils was then determined by measuring the change in fluorescence intensity. Interestingly, we found that a class of quinaldine-styryl scaffold compounds displays specific binding to beta-amyloid fibrils. A representative compound, STB-8, was used in ex vivo and in vivo imaging experiments on an AD transgenic mouse model and demonstrated excellent blood-brain barrier (BBB) permeability and specific staining of the AD beta-amyloid plaques
— id: 73943, year: 2007, vol: 8, page: 1679, stat: Journal Article,

Ligand binding and calcium influx induce distinct ectodomain/gamma -secretase processing pathways of EPHB2 receptor
Litterst, Claudia; Georgakopoulos, Anastasios; Shioi, Junichi; Ghersi, Enrico; Wisniewski, Thomas; Wang, Rong; Ludwig, Andreas; Robakis, Nikolaos K
2007 Jun 1;282(22):16155-16163, Journal of biological chemistry
Binding of EphB receptors to ephrinB ligands on the surface of adjacent cells initiates signaling cascades that regulate angiogenesis, axonal guidance and neuronal plasticity. These functions require processing of EphB receptors and removal of EphB-ephrinB complexes from the cell surface but the mechanisms involved are poorly understood. Here we show that the ectodomain of EphB2 receptor is released to extracellular space following cleavage after EphB2 residue 543. The remaining membrane-associated fragment is cleaved by the presenilin (PS)-dependent -secretase activity after EphB2 residue 569 releasing an intracellular peptide that contains the cytoplasmic domain of EphB2. This cleavage is inhibited by PS1 familial Alzheimer's disease mutations. Processing of EphB2 receptor depends on specific treatments: ephrinB ligand-induced processing requires endocytosis and the ectodomain cleavage is sensitive to peptide inhibitor ZVLL but insensitive to metalloproteinase inhibitor GM6001. The ligand-induced processing takes place in endosomes and involves the rapid degradation of the extracellular EphB2. EphrinB ligand stimulates ubiquitination of EphB2 receptor. Calcium influx- and NMDA-induced processing of EphB2 is inhibited by GM6001 and ADAM10 inhibitors but not by ZVLL. This processing requires no endocytosis and promotes rapid shedding of extracellular EphB2 indicating it takes place at the plasma membrane. Our data identify novel cleavages and modifications of EphB2 receptor and indicate that specific conditions determine the proteolytic systems and subcellular sites involved in the processing of this receptor
— id: 71396, year: 2007, vol: 282, page: 16155, stat: Journal Article,

Disease modifying approaches for Alzheimer's pathology
Sadowski, Marcin; Wisniewski, Thomas
2007 ;13(19):1943-1954, Current pharmaceutical design
Alzheimer's disease (AD) is the most common age-associated neurodegenerative disease in the world. The major neuropathological features of AD are synaptic loss, neuronal loss, neurofibrillary tangles and the deposition of amyloid-beta (Abeta) as plaques and in cerebral blood vessels. Numerous Abeta targeting therapeutic approaches have been shown to prevent amyloid deposition and resulting in cognitive improvement in transgenic mouse models of AD. Some of these approaches are currently in early clinical trials. It remains to be seen if these approaches will be proven effective in patients. Future anti-AD therapies will likely be multi-modal and individually tailored depending on the patient's immune status, genetic background and their amyloid burden, as determined by imaging studies using Abeta specific labeling ligands. Pre-clinical data suggests that it will be much more feasible to prevent AD related pathology, then to clear existing pathology, making early diagnosis critically important.
— id: 73005, year: 2007, vol: 13, page: 1943, stat: Journal Article,

Therapeutic monoclonal antibodies for prion exposure prophylaxis
Sadowski, MJ; Pankiewicz, J; Prelli, F; Scholtzova, H; Spinner, D; Kascsak, RB; Kascsak, RJ; Wisniewski, T
2007 ;68(12):A141-A142, Neurology
— id: 97601, year: 2007, vol: 68, page: A141, stat: Journal Article,

CpG oligodeoxynucleotide-enhanced humoral immune response and production of antibodies to prion protein PrPSc in mice immunized with 139A scrapie-associated fibrils
Spinner, Daryl S; Kascsak, Regina B; Lafauci, Giuseppe; Meeker, Harry C; Ye, Xuemin; Flory, Michael J; Kim, Jae Il; Schuller-Levis, Georgia B; Levis, William R; Wisniewski, Thomas; Carp, Richard I; Kascsak, Richard J
2007 Jun;81(6):1374-1385, Journal of leukocyte biology
Prion diseases are characterized by conversion of the cellular prion protein (PrP) to a protease-resistant conformer, the srapie form of PrP (PrP(Sc)). Humoral immune responses to nondenatured forms of PrP(Sc) have never been fully characterized. We investigated whether production of antibodies to PrP(Sc) could occur in PrP null (Prnp(-/-)) mice and further, whether innate immune stimulation with the TLR9 agonist CpG oligodeoxynucleotide (ODN) 1826 could enhance this process. Whether such stimulation could raise anti-PrP(Sc) antibody levels in wild-type (Prnp(+/+)) mice was also investigated. Prnp(-/-) and Prnp(+/+) mice were immunized with nondenatured 139A scrapie-associated fibrils (SAF), with or without ODN 1826, and were tested for titers of PrP-specific antibodies. In Prnp(-/-) mice, inclusion of ODN 1826 in the immunization regime increased anti-PrP titers more than 13-fold after two immunizations and induced, among others, antibodies, which were only present in the immune repertoire of mice receiving ODN 1826, to an N-terminal epitope. mAb 6D11, derived from such a mouse, reacted with the N-terminal epitope QWNK in native and denatured forms of PrP(Sc) and recombinant PrP and exhibited a Kd in the 10(-11) M range. In Prnp(+/+) mice, ODN 1826 increased anti-PrP levels as much as 84% after a single immunization. Thus, ODN 1826 potentiates adaptive immune responses to PrP(Sc) in 139A SAF-immunized mice. These results represent the first characterization of humoral immune responses to nondenatured, infectious PrP(Sc) and suggest methods for optimizing the generation of mAb to PrP(Sc), many of which could be used for diagnosis and treatment of prion diseases
— id: 71030, year: 2007, vol: 81, page: 1374, stat: Journal Article,

Mechanistic Insights into Prion Curing by Novel Anti-Prion Compounds
Webb, Sarah; Lekishvili, Tamuna; Loeschner, Corinna; Sellarajah, Shane; Prelli, Frances; Wisniewski, Thomas; Gilbert, Ian H; Brown, David R
2007 ;81(19):10729-10741, Journal of virology
Prion diseases are fatal neurodegenerative disorders. Identification of possible therapeutic tools is important in the search for a potential treatment for these diseases. Congo Red is an azo dye that has been used for many years to detect abnormal prion protein in the brains of diseased patients or animals. Congo Red has little therapeutic potential for the treatment of these diseases due to toxicity and poor permeation of the blood-brain-barrier. We have prepared two congo red derivatives designing out these liabilities with potent activity in cellular models of prion disease. One of these compounds cured cells of the transmissible agent. The mechanism of action of these compounds is possibly multifactorial. The high affinity of both ineffective and effective prion-curing Congo Red derivatives for abnormally folded prion protein suggests that the amyloidophylic property of these derivatives is not as critical to the mechanism of action as other effects. Effective prion-curing Congo Red derivatives increased degradation of abnormal PrP by the proteasome. Therefore the principal mechanism of action of the congo red analogues was to prevent inhibition of proteasomal activity by PrP(Sc)
— id: 73169, year: 2007, vol: 81, page: 10729, stat: Journal Article,

Intraneuronal Abeta immunoreactivity is not a predictor of brain amyloidosis-beta or neurofibrillary degeneration
Wegiel, Jerzy; Kuchna, Izabela; Nowicki, Krzysztof; Frackowiak, Janusz; Mazur-Kolecka, Bozena; Imaki, Humi; Wegiel, Jarek; Mehta, Pankaj D; Silverman, Wayne P; Reisberg, Barry; Deleon, Mony; Wisniewski, Thomas; Pirttilla, Tuula; Frey, Harry; Lehtimaki, Terho; Kivimaki, Tarmo; Visser, Frank E; Kamphorst, Wouter; Potempska, Anna; Bolton, David; Currie, Julia R; Miller, David L
2007 Apr;113(4):389-402, Acta neuropathologica
Amyloid beta (Abeta) immunoreactivity in neurons was examined in brains of 32 control subjects, 31 people with Down syndrome, and 36 patients with sporadic Alzheimer's disease to determine if intraneuronal Abeta immunoreactivity is an early manifestation of Alzheimer-type pathology leading to fibrillar plaque formation and/or neurofibrillary degeneration. The appearance of Abeta immunoreactivity in neurons in infants and stable neuron-type specific Abeta immunoreactivity in a majority of brain structures during late childhood, adulthood, and normal aging does not support this hypothesis. The absence or detection of only traces of reaction with antibodies against 4-13 aa and 8-17 aa of Abeta in neurons indicated that intraneuronal Abeta was mainly a product of alpha- and gamma-secretases (Abeta(17-40/42)). The presence of N-terminally truncated Abeta(17-40) and Abeta(17-42) in the control brains was confirmed by Western blotting and the identity of Abeta(17-40) was confirmed by mass spectrometry. The prevalence of products of alpha- and gamma -secretases in neurons and beta- and gamma-secretases in plaques argues against major contribution of Abeta-immunopositive material detected in neuronal soma to amyloid deposit in plaques. The strongest intraneuronal Abeta(17-42) immunoreactivity was observed in structures with low susceptibility to fibrillar Abeta deposition, neurofibrillary degeneration, and neuronal loss compared to areas more vulnerable to Alzheimer-type pathology. These observations indicate that the intraneuronal Abeta immunoreactivity detected in this study is not a predictor of brain amyloidosis or neurofibrillary degeneration. The constant level of Abeta immunoreactivity in structures free from neuronal pathology during essentially the entire life span suggests that intraneuronal amino-terminally truncated Abeta represents a product of normal neuronal metabolism
— id: 71032, year: 2007, vol: 113, page: 389, stat: Journal Article,

Is vaccination against transmissible spongiform encephalopathy feasible?
Wisniewski, T; Chabalgoity, J A; Goni, F
2007 Apr;26(1):243-251, Revue scientifique et technique (International Office of Epizootics)
Prion diseases are a unique category of illness, affecting both animals and humans, where the underlying pathogenesis is related to a conformation change of the cellular form of a normal, self-protein called a prion protein (PrP(c) [C for cellular]) to a pathological and infectious conformation known as scrapie form (PrPsc [Sc for scrapie]). Currently, all prion diseases are without effective treatment and are universally fatal. The emergence of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease has highlighted the need to develop possible therapies. In Alzheimer's disease (AD), which has similarities to prion diseases, both passive and active immunisation have been shown to be highly effective at preventing disease and cognitive deficits in model animals. In a human trial of active vaccination in AD, despite indications of cognitive benefits in patients with an adequate humoral response, 6% of patients developed significant complications related to excessive cell-mediated immunity. This experience highlights that immunotherapies designed to be directed against a self-antigen have to finely balance an effective humoral immune response with potential autoimmune toxicity. Many prion diseases have the gut as a portal of infectious agent entry. This makes mucosal immunisation a potentially very attractive method to partially or completely prevent prion entry across the gut barrier and to also produce a modulated immune response that is unlikely to be associated with any toxicity. The authors' recent results using an attenuated Salmonella vaccine strain expressing the prion protein show that mucosal vaccination can partially protect against prion infection from a peripheral source, suggesting the feasibility of this approach.
— id: 73007, year: 2007, vol: 26, page: 243, stat: Journal Article,

Mucosal vaccination can prevent prion infection via an oral route
Wisniewski, T; Prelli, F; Scholtzova, H; Wu, H; Chung, E; Chabalgoity, JA; Sigurdsson, E; Sadowski, M; Goni, F
2007 ;68(12):A348-A348, Neurology
— id: 97602, year: 2007, vol: 68, page: A348, stat: Journal Article,

Therapeutic approaches for prion and Alzheimer's diseases
Wisniewski, Thomas; Sigurdsson, Einar M
2007 Aug;274(15):3784-3798, FEBS journal
Alzheimer's and prion diseases belong to a category of conformational neurodegenerative disorders [Prusiner SB (2001) N Eng J Med344, 1516-1526; Sadowski M & Wisniewski T (2007) Curr Pharm Des 13, 1943-1954; Beekes M (2007) FEBS J 274, 575]. Treatments capable of arresting or at least effectively modifying the course of disease do not yet exist for either one of these diseases. Alzheimer's disease is the major cause of dementia in the elderly and has become an ever greater problem with the aging of Western societies. Unlike Alzheimer's disease, prion diseases are relatively rare. Each year only approximately 300 people in the USA and approximately 100 people in the UK succumb to various forms of prion diseases [Beekes M (2007) FEBS J 274, 575; Sigurdsson EM & Wisniewski T (2005) Exp Rev Vaccines 4, 607-610]. Nevertheless, these disorders have received great scientific and public interest due to the fact that they can be transmissible among humans and in certain conditions from animals to humans. The emergence of variant Creutzfeld-Jakob disease demonstrated the transmissibility of the bovine spongiform encephalopathy to humans [Beekes M (2007) FEBS J 274, 575]. Therefore, the spread of bovine spongiform encephalopathy across Europe and the recently identified cases in North America have put a large human population at risk of prion infection. It is estimated that at least several thousand Britons are asymptomatic carriers of prion infections and may develop variant Creutzfeld-Jakob disease in the future [Hilton DA (2006) J Pathol 208, 134-141]. This delayed emergence of human cases following the near elimination of bovine spongiform encephalopathy in the UK may occur because prion disease have a very prolonged incubation period, ranging from months to decades, which depends on the amount of inoculum, the route of infection and the genetic predisposition of the infected subject [Hilton DA (2006) J Pathol 208, 134-141]. Therefore, there is a great need for effective therapies for both Alzheimer's disease and prion diseases.
— id: 73006, year: 2007, vol: 274, page: 3784, 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,

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,

Clearance and prevention of prion infection in cell culture by anti-PrP antibodies
Pankiewicz, Joanna; Prelli, Frances; Sy, Man-Sun; Kascsak, Richard J; Kascsak, Regina B; Spinner, Daryl S; Carp, Richard I; Meeker, Harry C; Sadowski, Marcin; Wisniewski, Thomas
2006 May;23(10):2635-2647, European journal of neuroscience
Prion diseases are transmissible and invariably fatal neurodegenerative disorders associated with a conformational transformation of the cellular prion protein (PrP(C)) into a self-replicating and proteinase K (PK)-resistant conformer, scrapie PrP (PrP(Sc)). Humoral immunity may significantly prolong the incubation period and even prevent disease in murine models of prionoses. However, the mechanism(s) of action of anti-PrP monoclonal antibodies (Mabs) remain(s) obscure. The murine neuroblastoma N2a cell line, infected with the 22L mouse-adapted scrapie strain, was used to screen a large library of Mabs with similar binding affinities to PrP, to identify those antibodies which could clear established infection and/or prevent infection de novo. Three Mabs were found capable of complete and persistent clearing of already-infected N2a cells of PrP(Sc). These antibodies were 6D11 (generated to PK-resistant PrP(Sc) and detecting PrP residues 93-109), and 7H6 and 7A12, which were raised against recombinant PrP and react with neighbouring epitopes of PrP residues 130-140 and 143-155, respectively. Mabs were found to interact with PrP(Sc) formation both on the cell surface and after internalization in the cytosol. Treatment with Mabs was not associated with toxicity nor did it result in decreased expression of PrP(C). Both preincubation of N2a cells with Mabs prior to exposure to 22L inoculum and preincubation of the inoculum with Mabs prior to infecting N2a cells resulted in a significant reduction in PrP(Sc) levels. Information provided in these studies is important for the rational design of humoral immune therapy for prion infection in animals and eventually in humans
— id: 65120, year: 2006, vol: 23, page: 2635, stat: Journal Article,

Apolipoproteins in different amyloidoses
Sadowski M; Wisniewski T
Protein misfolding, aggregation, and conformational diseases. Part A. Protein aggretation and conformational diseases New York : Springer, 2006,
— id: 4979, year: 2006, vol: , page: 329, stat: Chapter,

Characterization of therapeutically effective monoclonal antibodies against prion protein
Sadowski, M; Pankiewicz, J; Prelli, F; Sy, MS; Kascsak, RJ; Kascsak, RB; Spinner, DS; Carp, RI; Meeker, HC; Wisniewski, T
2006 ;66(5):A258-A258, Neurology
— id: 97603, year: 2006, vol: 66, page: A258, stat: Journal Article,

Inhibition the apolipoprotein E/amyloid-beta interaction as a novel therapeutic approach for Alzheimer's disease
Sadowski, M; Pankiewicz, J; Scholtzova, H; Wen, P; Mehta, P; Quartermain, D; Wisniewski, T
2006 ;66(5):A379-A379, Neurology
— id: 97604, year: 2006, vol: 66, page: A379, stat: Journal Article,

Blocking the apolipoprotein E/amyloid-{beta} interaction as a potential therapeutic approach for Alzheimer's disease
Sadowski, Martin J; Pankiewicz, Joanna; Scholtzova, Henrieta; Mehta, Pankaj D; Prelli, Frances; Quartermain, David; Wisniewski, Thomas
2006 Dec 5;103(49):18787-18792, Proceedings of the National Academy of Sciences of the United States of America
The amyloid-beta (Abeta) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of Abeta peptide constitutes a critical event in the early disease pathogenesis. The direct binding between Abeta and apolipoprotein E (apoE) is an important factor implicated in both Abeta clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/Abeta interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed Abeta12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length Abeta. Abeta12-28P binds with high affinity to apoE, preventing its binding to Abeta, but has no direct effect on Abeta aggregation. Abeta12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of Abeta plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of Abeta in two AD transgenic mice models. The treatment did not affect the levels of soluble Abeta fraction or Abeta oligomers, indicating that inhibition of the apoE/Abeta interaction in vivo has a net effect of increasing Abeta clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with Abeta12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD
— id: 69282, year: 2006, vol: 103, page: 18787, stat: Journal Article,

Assessing the effects of memantine in APP/PS1 transgenic mice by behavioural studies and ex vivo imaging of amyloid plaques using gadolinium labelled amyloid beta peptides and mu MRI
Scholtzova, H; Wadghiri, YZ; Sigurdsson, EM; Douadi, M; Li, Y; Quartermain, D; Banerjee, PK; Wisniewski, T
2006 SEP ;16(11):S483-S483, European neuropsychopharmacology
— id: 69190, year: 2006, vol: 16, page: S483, stat: Journal Article,

Characterization and non-invasive imaging of lens b-amyloid in the Tg2576 mouse model of Alzheimer's disease
Goldstein, LE; Moir, R; Arnett, E; Sadowski, M; Tanzi, R; Wisniewski, T; Klunk, W; Clark, J; Chylack, LT
2005 ;46(Suppl. S):2905-A379, Investigative ophthalmology & visual science. IOVS
— id: 97605, year: 2005, vol: 46, page: 2905, stat: Journal Article,

Mucosal vaccination delays or prevents prion infection via an oral route
Goni, F; Knudsen, E; Schreiber, F; Scholtzova, H; Pankiewicz, J; Carp, R; Meeker, H C; Rubenstein, R; Brown, D R; Sy, M-S; Chabalgoity, J A; Sigurdsson, E M; Wisniewski, T
2005 ;133(2):413-421, Neuroscience
In recent years major outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP(C) (prion protein cellular), to a toxic and infectious form, PrP(Sc) (prion protein scrapie). None of the prionoses currently have an effective treatment. A limited number of active immunization approaches have been shown to slightly prolong the incubation period of prion infection. Active immunization in wild-type animals is hampered by auto-tolerance to PrP and potential toxicity. Here we report that mucosal vaccination with an attenuated Salmonella vaccine strain expressing the mouse PrP, is effective at overcoming tolerance to PrP and leads to a significant delay or prevention of prion disease in mice later exposed orally to the 139A scrapie strain. This mucosal vaccine induced gut anti-PrP immunoglobulin (Ig)A and systemic anti-PrP IgG. No toxicity was evident with this vaccination approach. This promising finding suggests that mucosal vaccination may be a useful method for overcoming tolerance to PrP and preventing prion infection among animal and potentially human populations at risk
— id: 75837, year: 2005, vol: 133, page: 413, stat: Journal Article,

An aggregation-specific enzyme-linked immunosorbent assay: detection of conformational differences between recombinant PrP protein dimers and PrP(Sc) aggregates
Pan, Tao; Chang, Binggong; Wong, Poki; Li, Chaoyang; Li, Ruliang; Kang, Shin-Chung; Robinson, John D; Thompsett, Andrew R; Tein, Po; Yin, Shaoman; Barnard, Geoff; McConnell, Ian; Brown, David R; Wisniewski, Thomas; Sy, Man-Sun
2005 Oct;79(19):12355-12364, Journal of virology
The conversion of the normal cellular prion protein, PrP(C), into the protease-resistant, scrapie PrP(Sc) aggregate is the cause of prion diseases. We developed a novel enzyme-linked immunosorbent assay (ELISA) that is specific for PrP aggregate by screening 30 anti-PrP monoclonal antibodies (MAbs) for their ability to react with recombinant mouse, ovine, bovine, or human PrP dimers. One MAb that reacts with all four recombinant PrP dimers also reacts with PrP(Sc) aggregates in ME7-, 139A-, or 22L-infected mouse brains. The PrP(Sc) aggregate is proteinase K resistant, has a mass of 2,000 kDa or more, and is present at a time when no protease-resistant PrP is detectable. This simple and sensitive assay provides the basis for the development of a diagnostic test for prion diseases in other species. Finally, the principle of the aggregate-specific ELISA we have developed may be applicable to other diseases caused by abnormal protein aggregation, such as Alzheimer's disease or Parkinson's disease
— id: 64338, year: 2005, vol: 79, page: 12355, stat: Journal Article,

Biochemical fingerprints of prion infection: accumulations of aberrant full-length and N-terminally truncated PrP species are common features in mouse prion disease
Pan, Tao; Wong, Poki; Chang, Binggong; Li, Chaoyang; Li, Ruliang; Kang, Shin-Chung; Wisniewski, Thomas; Sy, Man-Sun
2005 Jan;79(2):934-943, Journal of virology
Infection with any one of three strains of mouse scrapie prion (PrPSc), 139A, ME7, or 22L, results in the accumulation of two underglycosylated, full-length PrP species and an N-terminally truncated PrP species that are not detectable in uninfected animals. The levels of the N-terminally truncated PrP species vary depending on PrPSc strain. Furthermore, 22L-infected brains consistently have the highest levels of proteinase K (PK)-resistant PrP species, followed by ME7- and 139A-infected brains. The three strains of PrPSc are equally susceptible to PK and proteases papain and chymotrypsin. Their protease resistance patterns are also similar. In sucrose gradient velocity sedimentation, the aberrant PrP species partition with PrPSc aggregates, indicating that they are physically associated with PrPSc. In ME7-infected animals, one of the underglycosylated, full-length PrP species is detected much earlier than the other, before both the onset of clinical disease and the detection of PK-resistant PrP species. In contrast, the appearance of the N-terminally truncated PrP species coincides with the presence of PK-resistant species and the manifestation of clinical symptoms. Therefore, accumulation of the underglycosylated, full-length PrP species is an early biochemical fingerprint of PrPSc infection. Accumulation of the underglycosylated, full-length PrP species and the aberrant N-terminally truncated PrP species may be important in the pathogenesis of prion disease
— id: 64339, year: 2005, vol: 79, page: 934, stat: Journal Article,

Anti-PrP monoclonal antibodies for prevention of prion infection
Pankiewicz, J; Prelli, F; Sadowski, M; Scholtzova, H; Kascsak, R; Kascsak, R; Carp, RI; Meeker, CH; Sy, MS; Wisniewski, T
2005 ;64(6):A249-A250, Neurology
— id: 97606, year: 2005, vol: 64, page: A249, stat: Journal Article,

MRI approaches for specific targeting of PrPSc in the spleen of prion infected presymptomatic subjects
Sadowski, M; Wadghiri, ZY; Brown, D; Scholtzova, H; Pankiewicz, J; Turnbull, DH; Wisniewski, T
2005 ;64(6):A409-A410, Neurology
— id: 97607, year: 2005, vol: 64, page: A409, stat: Journal Article,

Therapeutics and prion disease: Can immunisation or drugs be effective?
Sassoon, J; Sadowski, M; Wisniewski, T; Brown, DR
2005 APR ;5(4):361-366, Mini reviews in medicinal chemistry
Prion diseases are of considerable importance because of the threat of a variant form of Creutzfeldt Jakob disease that has emerged in recent years. Pre-clinical diagnosis of prion diseases still remains poor and effective therapies also do not exist at present. This review examines research on possible therapeutic strategies that might have potential benefits if applied before neurodegeneration has occurred
— id: 50153, year: 2005, vol: 5, page: 361, stat: Journal Article,

Promising developments in prion immunotherapy
Sigurdsson, Einar M; Wisniewski, Thomas
2005 Oct;4(5):607-610, Expert review of vaccines
— id: 62131, year: 2005, vol: 4, page: 607, stat: Journal Article,

Magnetic resonance imaging of amyloid plaques in transgenic mice
Wadghiri, Youssef Zaim; Sigurdsson, Einar M; Wisniewski, Thomas; Turnbull, Daniel H
2005 ;299:365-379, Methods in molecular biology
Transgenic mice are used increasingly to model brain amyloidosis, mimicking the pathogenic processes involved in Alzheimer's disease (AD). In this chapter, a strategy is described that has been successfully used to map amyloid deposits in transgenic mouse models of AD with magnetic resonance imaging (MRI), utilizing molecular targeting vectors labeled with MRI contrast agents to enhance selectively the signal from amyloid plaques. To obtain sufficient spatial resolution for effective and sensitive mouse brain imaging, magnetic fields of 7-Tesla (T) or more are required. These are higher than the 1.5-T field strength routinely used for human brain imaging. The higher magnetic fields affect contrast agent efficiency, and determine the choice of pulse sequence parameters for in vivo MRI, all addressed in this chapter. Ex vivo imaging is also described as an important step to test and optimize protocols prior to in vivo studies. The experimental setup required for mouse brain imaging is explained in detail, including anesthesia, immobilization of the mouse head to reduce motion artifacts, and anatomical landmarks to use for the slice alignment procedure to improve image co-registration during longitudinal studies, and for subsequent matching of MRI with histology
— id: 56371, year: 2005, vol: 299, page: 365, stat: Journal Article,

Is amyloid-beta-peptide immunization clinically effective in patients with Alzheimer's disease?
Wisniewski, Thomas
2005 Dec;1(2):84-85, Nature clinical practice. Neurology
— id: 68666, year: 2005, vol: 1, page: 84, 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,

A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 (Pro117Ser): Comparison of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations
Dowjat, Wieslaw K; Kuchna, Izabela; Wisniewski, Thomas; Wegiel, Jerzy
2004 Feb;6(1):31-43, Journal of Alzheimer's Disease
A novel presenilin-1 (PS1) mutation (P117S) in an American pedigree is described. We compare clinical, neuropathological and cell culture phenotypes produced by this mutation with another codon 117 mutation that was earlier discovered by our group in a Polish kindred. Both mutations are associated with an unusually severe Alzheimer disease (AD) phenotype, with the onset starting before the third decade of life, rapid disease progression and acute presentation of clinical symptoms. The severity of clinical phenotype was closely correlated with the abundance of pathology: massive deposition of Abeta42 in plaques, severe neurofibrillary degeneration and neuronal loss. When overexpressed in mouse neuroblastoma N2a cells, both mutations caused loss of an ability to promote neurite outgrowth and produced an increase in the ratio of secreted Abeta42/40 amyloid peptides. In stably transfected N2a cell lines only mutant proteins were endoproteolytically cleaved indicating some dependability of this process on the presence of mutation. Taken together, our results show that clinical and cell culture phenotypes produced by these 2 codon 117 mutations are closely related suggesting that the pathogenic action of PS1 may involve effect on neurite outgrowth and endoproteolytic cleavage of the full-length protein. Given the high potency in vivo and in vitro of both codon 117 mutations, this site of PS1 must be particularly important for its normal/pathogenic function
— id: 45287, year: 2004, vol: 6, page: 31, 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,

An animal model of vascular amyloidosis
Ghiso, Jorge; Wisniewski, Thomas
2004 Sep;7(9):902-904, Nature neuroscience
— id: 44510, year: 2004, vol: 7, page: 902, stat: Journal Article,

MRI assessment of neuropathology in a transgenic mouse model of Alzheimer's disease
Helpern, Joseph A; Lee, Sang-Pil; Falangola, Maria F; Dyakin, Victor V; Bogart, Adam; Ardekani, Babak; Duff, Karen; Branch, Craig; Wisniewski, Thomas; de Leon, Mony J; Wolf, Oliver; O'Shea, Jacqueline; Nixon, Ralph A
2004 Apr;51(4):794-798, Magnetic resonance in medicine
The cerebral deposition of amyloid beta-peptide, a central event in Alzheimer's disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Noninvasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. In this study, high-field MRI was used to detect changes in regional brain MR relaxation times in three types of mice: 1). transgenic mice (PS/APP) carrying both mutant genes for amyloid precursor protein (APP) and presenilin (PS), which have high levels and clear accumulation of beta-amyloid in several brain regions, starting from 10 weeks of age; 2). transgenic mice (PS) carrying only a mutant gene for presenilin (PS), which show subtly elevated levels of Abeta-peptide without beta-amyloid deposition; and 3). nontransgenic (NTg) littermates as controls. The transverse relaxation time T(2), an intrinsic MR parameter thought to reflect impaired cell physiology, was significantly reduced in the hippocampus, cingulate, and retrosplenial cortex, but not the corpus callosum, of PS-APP mice compared to NTg. No differences in T(1) values or proton density were detected between any groups of mice. These results indicate that T(2) may be a sensitive marker of abnormalities in this transgenic mouse model of AD
— id: 42285, year: 2004, vol: 51, page: 794, stat: Journal Article,

Prion protein is ubiquitinated after developing protease resistance in the brains of scrapie-infected mice
Kang, Shin-Chung; Brown, David R; Whiteman, Matthew; Li, Ruliang; Pan, Tao; Perry, George; Wisniewski, Thomas; Sy, Man-Sun; Wong, Boon-Seng
2004 May;203(1):603-608, Journal of pathology
Although the key event in the pathology of prion diseases is thought to be the conversion of cellular prion protein (PrP(C)) to the protease-resistant scrapie species termed PrP(Sc), the factors that contribute to neurodegeneration in scrapie-infected animals are poorly understood. One probable determinant could be when the accumulation of PrP(Sc) in infected brain overwhelms the ubiquitin-proteasome system and triggers the degenerative cascade. In the present study, it was found that in mouse brains infected with the ME7 scrapie strain, the level of ubiquitin protein conjugates increased significantly at approximately 144 days post-infection (pi) when clinical signs first become apparent. This elevation correlated with the detection of protease-resistant PrP(Sc) and a decline in two endopeptidase activities associated with proteasome function. However, ubiquitination of PrP was only detected at the terminal stage, 3 weeks after the development of clinical symptoms ( approximately 165 days pi). These results suggest that ubiquitination of PrP is a late event phenomenon and this conjugation occurs after the formation of protease-resistant PrP(Sc). Whether this post-translational modification and the impairment of proteasome function are pivotal events in the pathogenesis of prion diseases remains to be determined.
— id: 42679, year: 2004, vol: 203, page: 603, stat: Journal Article,

Intraneuronal amyloid beta immunoreactivity is not a predictor of fibrillar plaque formation or neurofibrillary degeneration
Kuchna, I; Nowicki, K; Imaki, H; Wang, KC; Mehta, PD; Silverman, WP; Reisberg, B; de Leon, M; Wisniewski, T; Pirttila, T; Frey, H; Lehtimaki, T; Kivimaki, T; Visser, FE; Kamphorst, W; Currie, JR; Miller, DL; Wegiel, J
2004 JUL ;25(10):S407-S408, Neurobiology of aging
— id: 47737, year: 2004, vol: 25, page: S407, stat: Journal Article,

Epitope scanning reveals gain and loss of strain specific antibody binding epitopes associated with the conversion of normal cellular prion to scrapie prion
Pan, Tao; Li, Ruliang; Kang, Shin-Cheng; Wong, Boon-Seng; Wisniewski, Thomas; Sy, Man-Sun
2004 Sep;90(5):1205-1217, Journal of neurochemistry
We used anti-prion (PrP) monoclonal antibodies (Mabs) in different combinations to scan changes in the availability of antibody binding epitopes--using an epitope scanning assay--in brain homogenates from normal mice, and from mice infected with either ME7 or 139 A strains of infectious scrapie prion (PrPSc). In ME7-infected brains, the epitope detected by the Mab pair 8B4/8H4 is reduced, while the epitope detected by the Mab pair 8F9/11G5 is increased. Mab 8F9/11G5 detect a conformational epitope on PrPSc because the rise in Mab 8F9/11G5 binding is sensitive to a denaturing agent but resistant to proteinase K (PK). While the increase in Mab 8F9/11G5 binding correlates with the presence of PK-resistant PrP and clinical signs of infection, the reduction in Mab 8B4/8H4 binding is detected earlier. Fractionation of the ME7-infected brain homogenate in sucrose gradient revealed that the PrPSc species detected by the epitope scanning assay are heterogeneous in size, with a molecular mass of approximately > or = 2000-kDa. We also investigated whether these findings were applicable to two other strains of PrPSc, namely 87 V and 22 L. We found that the decrease in Mab 8B4/8H4 binding detected in ME7-infected brains was also detected in 87 V-infected brains but not in 22 L-infected brains. In contrast, the increase in Mab 8F9/11G5 binding detected in ME7- and 139 A-infected brains was also detected in 22 L-infected brains but not in 87 V-infected brains. Therefore, each prion strain has its unique conformation, and we can monitor the conversion of normal cellular prion (PrPC) to PrPSc based on the changes in the antibody binding patterns. The epitope can be decreased or increased, linear or conformational, detected late or early during infection, in a strain specific manner
— id: 45286, year: 2004, vol: 90, page: 1205, stat: Journal Article,

Monoclonal antibodies for the treatment of prion infection
Pankiewicz, J; Prelli, F; Scholtzova, H; Sadowski, M; Sigurdsson, EM; Goni, F; Kascsak, R; Kascsak, R; Carp, RI; Meeker, HC; Sy, MS; Wisniewski, T
2004 JUL ;25(10):S456-S456, Neurobiology of aging
— id: 47740, year: 2004, vol: 25, page: S456, stat: Journal Article,

Prion diseases
Sadowski M; Verma A; Wisniewski T
Neurology in clinical practice Philadelphia : Butterworth-Heinemann, 2004,
— id: 3167, year: 2004, vol: , page: 1613, stat: Chapter,

100 questions and answers about Alzheimer's disease
Sadowski M; Wisniewski T
Boston : Jones & Bartlett, 2004,
— id: 763, year: 2004, vol: , page: , stat: ,

Blocking the apolipoprotein E/beta-amyloid interaction by synthetic peptide mitigates beta-amyloid toxicity and fibril formation in vitro and in vivo
Sadowski, M; Pankiewicz, J; Scholtzova, H; Li, Y; Sigurdsson, EM; Wisniewski, T
2004 AUG ;13(3):237-237, Protein science
— id: 55684, year: 2004, vol: 13, page: 237, stat: Journal Article,

In vivo imaging of prion amyloid deposits
Sadowski, M; Pankiewicz, J; Scholtzova, H; Tsai, J; Carp, RI; Meeker, HC; Debnath, M; Mathis, CA; Shao, L; Klunk, WE; Gan, WB; Wisniewski, T
2004 JUL ;25(10):S280-S281, Neurobiology of aging
— id: 47732, year: 2004, vol: 25, page: S280, stat: Journal Article,

Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Ji, Yong; Quartermain, David; Jensen, Catrin H; Duff, Karen; Nixon, Ralph A; Gruen, Rand J; Wisniewski, Thomas
2004 May;63(5):418-428, Journal of neuropathology & experimental neurology
In Alzheimer disease (AD) patients, early memory dysfunction is associated with glucose hypometabolism and neuronal loss in the hippocampus. Double transgenic (Tg) mice co-expressing the M146L presenilin 1 (PS1) and K670N/M671L, the double 'Swedish' amyloid precursor protein (APP) mutations, are a model of AD amyloid-beta deposition (Abeta) that exhibits earlier and more profound impairments of working memory and learning than single APP mutant mice. In this study we compared performance on spatial memory tests, regional glucose metabolism, Abeta deposition, and neuronal loss in APP/PS1, PS1, and non-Tg (nTg) mice. At the age of 2 months no significant morphological and metabolic differences were detected between 3 studied genotypes. By 8 months, however, APP/PS1 mice developed selective impairment of spatial memory, which was significantly worse at 22 months and was accompanied by reduced glucose utilization in the hippocampus and a 35.8% dropout of neurons in the CA1 region. PS1 mice exhibited a similar degree of neuronal loss in CA1 but minimal memory deficit and no impairment of glucose utilization compared to nTg mice. Deficits in 22 month APP/PS1 mice were accompanied by a substantially elevated Abeta load, which rose from 2.5% +/- 0.4% at 8 months to 17.4% +/- 4.6%. These findings implicate Abeta or APP in the behavioral and metabolic impairments in APP/PS1 mice and the failure to compensate functionally for PS1-related hippocampal cell loss
— id: 44514, year: 2004, vol: 63, page: 418, stat: Journal Article,

Links between the pathology of Alzheimer's disease and vascular dementia
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Li, Yong-sheng; Quartermain, David; Duff, Karen; Wisniewski, Thomas
2004 Jul;29(6):1257-1266, Neurochemical research
The major neuropathological lesions defining Alzheimer's disease (AD) include neurofibrillary tangles and amyloid plaques, which are mainly composed of abnormally phosphorylated tau and amyloid-beta (A beta), respectively. Numerous neuropathological and neuroimaging studies indicate that at least one-third of AD cases are complicated by some degree of vascular pathology, whereas in a similar proportion of patients clinically diagnosed with vascular dementia, AD pathology is also present. Many classical vascular risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia have recently been shown also to increase the risk of AD. Growing evidence suggests that vascular pathology lowers the threshold for the clinical presentation of dementia at a given level of AD-related pathology and potentially directly promotes AD lesions such as A beta plaques. Cerebral ischemia, chronically up-regulates expression of the amyloid precursor protein (APP), which is the precursor to the amyloid beta peptide and damages the blood-brain barrier (BBB), affecting A beta peptide clearance from the brain. Recognition of the importance of these vascular risk factors for AD-related dementia and their treatment will be beneficial not only for preventing cardiac, cerebral, and peripheral complications of vascular disease, but also will likely have a direct impact on the occurrence of sporadic AD in older subjects. In this paper, we review some of the links between vascular risk factors and AD pathology and present data on the direct effect of ischemia on cognitive function and A beta deposition in a mouse model of AD
— id: 46031, year: 2004, vol: 29, page: 1257, stat: Journal Article,

Blocking the chaperoning effect of apolipoprotein E reduces beta-amyloid load in Alzheimer's disease transgenic mice
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Ripellino, James A.; Schmidt, Stephen D.; Mathews, Paul W.; Sigurdsson, Einar M.; Wisniewski, Thomas
2004 ;62(7, Suppl. 5):A522-A447, Neurology
— id: 97610, year: 2004, vol: 62, page: A522, stat: Journal Article,

A Synthetic Peptide Blocking the Apolipoprotein E/{beta}-Amyloid Binding Mitigates {beta}-Amyloid Toxicity and Fibril Formation in Vitro and Reduces {beta}-Amyloid Plaques in Transgenic Mice
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Ripellino, James A; Li, Yongsheng; Schmidt, Stephen D; Mathews, Paul M; Fryer, John D; Holtzman, David M; Sigurdsson, Einar M; Wisniewski, Thomas
2004 Sep;165(3):937-948, American journal of pathology
Alzheimer's disease (AD) is associated with accumulation of beta-amyloid (Abeta). A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele. ApoE can act as a pathological chaperone of Abeta, promoting its conformational transformation from soluble Abeta into toxic aggregates. We determined if blocking the apoE/Abeta interaction reduces Abeta load in transgenic (Tg) AD mice. The binding site of apoE on Abeta corresponds to residues 12 to 28. To block binding, we synthesized a peptide containing these residues, but substituted valine at position 18 to proline (Abeta12-28P). This changed the peptide's properties, making it non-fibrillogenic and non-toxic. Abeta12-28P competitively blocks binding of full-length Abeta to apoE (IC(50) = 36.7 nmol). Furthermore, Abeta12-28P reduces Abeta fibrillogenesis in the presence of apoE, and Abeta/apoE toxicity in cell culture. Abeta12-28P is blood-brain barrier-permeable and in AD Tg mice inhibits Abeta deposition. Tg mice treated with Abeta12-28P for 1 month had a 63.3% reduction in Abeta load in the cortex (P = 0.0043) and a 59.5% (P = 0.0087) reduction in the hippocampus comparing to age-matched control Tg mice. Antibodies against Abeta were not detected in sera of treated mice; therefore the observed therapeutic effect of Abeta12-28P cannot be attributed to an antibody clearance response. Our experiments demonstrate that compounds blocking the interaction between Abeta and its pathological chaperones may be beneficial for treatment of beta-amyloid deposition in AD
— id: 44511, year: 2004, vol: 165, page: 937, stat: Journal Article,

Detection of prion amyloid deposits in vivo
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Tsai, Julia; Carp, Richard I.; Meeker, Cliff H.; Gan, Wen-Biao; Klunk, William E.; Mathis, Chester A.; Shao, Li; Debnath, Manik; Wisniewski, Thomas
2004 ;62(7, Suppl. 5):A446-A447, Neurology
— id: 97609, year: 2004, vol: 62, page: A446, stat: Journal Article,

Targeting prion amyloid deposits in vivo
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Tsai, Julia; Li, Yongsheng; Carp, Richard I; Meeker, Harry C; Gambetti, Pierluigi; Debnath, Manik; Mathis, Chester A; Shao, Li; Gan, Wen-Biao; Klunk, William E; Wisniewski, Thomas
2004 Jul;63(7):775-784, Journal of neuropathology & experimental neurology
The diagnosis of prion diseases in humans is challenging due to a lack of specific and sensitive non-invasive tests. Many forms of human prion disease including variant Creutzfeldt-Jakob disease (vCJD), Gerstmann-Straussler-Scheinker (GSS) syndrome, and 10% of sporadic CJD cases are associated with amyloid deposition. Several positron emission tomography (PET) ligands have recently been developed to directly image beta-amyloid associated with Alzheimer disease. One of them, methoxy-X04, is a fluorescent derivative of Congo red with high binding affinity toward amyloid fibrils and good blood-brain barrier permeability. Using methoxy-X04, we investigated whether amyloid-targeting ligands can be also employed for direct imaging of amyloid deposits associated with some prion diseases. Such a method could potentially become a novel diagnostic approach for these conditions. Studies were performed on MB mice infected with the 87V mouse-adapted scrapie strain. Labeling of PrP amyloid plaques in brains of presymptomatic and symptomatic mice was demonstrated using in vivo transcranial two-photon microscopy after systemic administration of methoxy-X04. During real-time imaging, PrP amyloid deposits could be clearly distinguished 15 min after intravenous administration of methoxy-X04. The ligand showed rapid clearance from brain areas that did not contain amyloid deposits. PrP amyloid deposits could also be detected by direct application of methoxy-X04 on cerebellar sections from GSS patients. These results suggest that methoxy-X04 or similar derivatives could be used as PET imaging agents to improve the diagnosis of human prion diseases associated with amyloid deposition
— id: 44512, year: 2004, vol: 63, page: 775, stat: Journal Article,

Vaccines for conformational disorders
Sadowski, Marcin; Wisniewski, Thomas
2004 ;3(3):279-90, Expert review of vaccines
Neurodegenerative disorders are becoming increasingly common and an ever greater healthcare burden, as the average age in Western populations rises. Many of these are conformational disorders, which are characterized by the accumulation of a host protein that undergoes a structural change increasing its beta-sheet content, rendering it toxic. The most common of these illnesses is Alzheimer's disease. Prion diseases are also conformational disorders, which are currently less common than Alzheimer's disease, however, these illnesses have no treatment and are universally rapidly fatal. The emergence of new variant Creutzfeldt-Jakob disease has raised the possibility of a large population at risk for this illness, as well as causing great concern regarding the safety of blood bank supplies. Recently, immune modulation has emerged as a highly promising therapeutic strategy for both Alzheimer's and prion diseases. We and others have demonstrated in both Alzheimer's and prion disease animal models that vaccination can dramatically improve the course of the illness. A human trial of an Alzheimer's disease vaccine using A beta1-42 was halted due to toxicity in a minority of patients (6%). However, recent data suggests that patients with a humoral response to A beta benefited cognitively from the vaccine. Toxicity in this human trial has been linked to excessive cell-mediated immunity. Novel vaccine strategies are under development for both Alzheimer's disease and prionoses which are predicted to have few or no significant side effects, while being efficacious. $$:
— id: 97608, year: 2004, vol: 3, page: 279, stat: Journal Article,

Age-associated behavioral, metabolic, and structural changes in wild-type littermates of Alzheimer's transgenic mice
Scholtzova, H; Pankiewicz, J; Sadowski, M; Quartermain, D; Jensen, CH; Duff, K; Nixon, RA; Helpern, JH; Gruen, RJ; Wisniewski, T
2004 JUL ;25(10):S225-S226, Neurobiology of aging
— id: 47726, year: 2004, vol: 25, page: S225, stat: Journal Article,

In vivo magnetic resonance of amyloid plaques in Alzheimer's disease model mice
Sigurdsson, E; Wadghiri, YZ; Sadowski, M; Elliott, JI; Li, YS; Scholtzova, H; Tang, CY; Aguinaldo, G; Duff, K; Turnbull, DH; Wisniewski, T
The living brain and Alzheimer's disease Berlin : Springer, 2004,
A key feature of Alzheimer's disease (AD) is the deposition of the amyloid beta (Abeta) as neuritic plaques in the brain. Transgenic mice overexpressing mutant amyloid precursor protein (APP), or both mutant APP and presenilin-1 (APP-PS1), develop Abeta plaques similar to AD patients and are currently the most widely used models of AD. The definitive diagnosis of AD still requires post-mortem examination. We have developed a novel method for the detection of Abeta plaques in the brains of AD model transgenic mice using magnetic resonance micro-imaging (muMRI). Our method is dependent on ligands that bind to AD amyloid lesions, allowing their detection by muMRI. These ligands are Abeta1-40 peptides, magnetically labeled with either gadolinium (Gd) or monocrystalline iron oxide nanoparticles (MION). When these are systemically injected with mannitol to transiently open the blood-brain barrier, we are able to detect the majority of amyloid lesions. The number of lesions detected by muMRI showed a statistically significant correlation with the Abeta burden determined by histology. This approach, with additional development, may be used to detect amyloid lesions in humans. Similar methods may also be used to image other conformational neurodegenerative disorders
— id: 4970, year: 2004, vol: , page: 47, stat: Chapter,

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,

In vivo magnetic resonance imaging of amyloid plaques in mice with a non-toxic A beta derivative
Sigurdsson, EM; Wadghiri, YZ; Blind, JA; Knudsen, E; Asuni, A; Sadowski, M; Turnbull, DH; Wisniewski, T
2004 JUL ;25(10):S57-S57, Neurobiology of aging
— id: 47715, year: 2004, vol: 25, page: S57, stat: Journal Article,

Detection of Alzheimer's amyloid lesions in transgenic mice by magnetic resonance imaging
Sigurdsson, EM; Wadghiri, YZ; Li, YS; Elliott, JI; Tang, CY; Aguilnaldo, G; Duff, K; Pappolla, M; Watanabe, M; Scholtzova, H; Turnbull, DH; Wisniewski, T
2004 FEB ;25(2):251-251, Neurobiology of aging
— id: 42486, year: 2004, vol: 25, page: 251, stat: Journal Article,

Age-associated neurofibrillary degeneration and neuronal loss in people free of beta-amyloidosis
Wegiel, J; Kuchna, I; Nowicki, K; Badmaev, E; Wisniewski, T; de Leon, M; Reisberg, B; Pirttila, T; Silverman, WP
2004 JUL ;25(10):S10-S10, Neurobiology of aging
— id: 47707, year: 2004, vol: 25, page: S10, stat: Journal Article,

Cell type- and brain structure-specific patterns of distribution of minibrain kinase in human brain
Wegiel, Jerzy; Kuchna, Izabela; Nowicki, Krzysztof; Frackowiak, Janusz; Dowjat, Karol; Silverman, Wayne P; Reisberg, Barry; DeLeon, Mony; Wisniewski, Thomas; Adayev, Tatyana; Chen-Hwang, Mo-Chou; Hwang, Yu-Wen
2004 Jun 4;1010(1-2):69-80, Brain research
The minibrain kinase (Mnb/Dyrk1A) gene is localized in the Down syndrome (DS) critical region of chromosome 21. This gene encodes a proline-directed serine/threonine protein kinase (minibrain kinase-Mnb/Dyrk1A), which is required for the proliferation of distinct neuronal cell types during postembryonic neurogenesis. To study the distribution of Mnb/Dyrk1A during human brain development and aging, we raised Mnb/Dyrk1A-specific antibody (mAb 7F3) and examined 22 brains of normal subjects from 8 months to 90 years of age. We found that neurons were the only cells showing the presence of 7F3-positive product in both cell nucleus and cytoplasm. Nuclear localization supports the concept that Mnb/Dyrk1A may be involved in control of gene expression. Synaptic localization of Mnb/Dyrk1A also supports our previous studies suggesting that Mnb/Dyrk1A is a regulator of assembly of endocytic apparatus and appears to be involved in synaptic vesicle recycling and synaptic signal transmission. Accumulation of numerous 7F3-positive corpora amylacea in the memory and motor system subdivisions in subjects older than 33 years of age indicates that Mnb/Dyrk1A is colocalized with markers of astrocyte and neuron degeneration. Differences in the topography and the amount of Mnb/Dyrk1A in neurons, astrocytes, and ependymal and endothelial cells appear to reflect cell type- and brain structure-specific patterns in trafficking and utilization of Mnb/Dyrk1A
— id: 44515, year: 2004, vol: 1010, page: 69, 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,

Reduction of beta-amyloid load in Alzheimer's disease transgenic mice by competitive blocking of beta-amyloid binding to apolipoprotein E
Wisniewski, T; Pankiewicz, J; Scholtzova, H; Schmidt, SD; Mathews, PM; Sigurdsson, EM; Sadowski, M
2004 JUL ;25(10):S583-S583, Neurobiology of aging
— id: 47746, year: 2004, vol: 25, page: S583, stat: Journal Article,

In vivo imaging of amyloid plaques in AD and prion disease model mice
Wisniewski, T; Sigurdsson, EM; Wadghiri, YZ; Carp, R; Tang, CY; Turnbull, DH; Mathis, C; Klunk, WE; Gan, WB; Sadowski, M
2004 APR ;25(12):S29-S29, Neurobiology of aging
— id: 42446, year: 2004, vol: 25, page: S29, stat: Journal Article,

Prion protein ubiquitination in scrapie infection
Wong, BS; Kang, SC; Brown, DR; Whiteman, M; Li, R; Pan, T; Perry, G; Wisniewski, T; Sy, MS
2004 FEB ;88(5):55-55, Journal of neurochemistry
— id: 42488, year: 2004, vol: 88, page: 55, stat: Journal Article,

Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients
Ji, Y; Gong, Y; Gan, W; Beach, T; Holtzman, D M; Wisniewski, T
2003 ;122(2):305-315, Neuroscience
Dendritic spines are postsynaptic sites of excitatory input in the mammalian nervous system. Apolipoprotein (apo) E participates in the transport of plasma lipids and in the redistribution of lipids among cells. A role for apoE is implicated in regeneration of synaptic circuitry after neural injury. The apoE4 allele is a major risk factor for late-onset familial and sporadic Alzheimer's disease (AD) and is associated with a poor outcome after brain injury. ApoE isoforms are suggested to have differential effects on neuronal repair mechanisms. In vitro studies have demonstrated the neurotrophic properties of apoE3 on neurite outgrowth. We have investigated the influence of apoE genotype on neuronal cell dendritic spine density in mice and in human postmortem tissue. In order to compare the morphology of neurons developing under different apoE conditions, gene gun labeling studies of dendritic spines of dentate gyrus (DG) granule cells of the hippocampus were carried out in wild-type (WT), human apoE3, human apoE4 expressing transgenic mice and apoE knockout (KO) mice; the same dendritic spine parameters were also assessed in human postmortem DG from individuals with and without the apoE4 gene. Quantitative analysis of dendritic spine length, morphology, and number was carried out on these mice at 3 weeks, 1 and 2 years of age. Human apoE3 and WT mice had a higher density of dendritic spines than human E4 and apoE KO mice in the 1 and 2 year age groups (P<0.0001), while at 3 weeks there were no differences between the groups. These age dependent differences in the effects of apoE isoforms on neuronal integrity may relate to the increased risk of dementia in aged individuals with the apoE4 allele. Significantly in human brain, apoE4 dose correlated inversely with dendritic spine density of DG neurons cell in the hippocampus of both AD (P=0.0008) and aged normal controls (P=0.0015). Our findings provide one potential explanation for the increased cognitive decline seen in aged and AD patients expressing apoE4
— id: 46270, year: 2003, vol: 122, page: 305, stat: Journal Article,

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,

Global ischemia exacerbates Alzheimer's disease related pathology in transgenic mice
Pankiewicz, J.; Scholtzova, H.; Sadowski, M.; Ferris, S.; Li, Y. S.; Quartermain, D.; Duff, K.; Wisniewski, T.
2003 ;2003(7, Suppl. 5):Abstract No. 534.7-S583, Society for Neuroscience Abstract Viewer & Itinerary Planner
A significant percentage of Alzheimer's disease (AD) patients exhibit concomitant vascular pathology. Epidemiological evidence suggest that vascular disease may not only add to global cognitive impairment but also exacerbate the course of AD pathology. The goal of this study was to analyze the impact of global ischemia on the cellular and amyloid-beta pathology in AD murine transgenic (Tg) models. Seven month old double Tg mice, expressing Swedish amyloid precursor protein (APP) and M146L presenilin 1 (PS1) mutations and single Tg mice (PS1 mutation alone) were subjected to 45 minutes bilateral common carotid artery occlusion or sham surgery. Behavioral testing performed two weeks after the surgery showed impaired learning and memory retention on Morris water maze and Hebb-Williams tests in both single PS1 and double PS1/APP Tg mice which underwent ischemia comparing to sham operated animals (p<0.05). Double Tg mice scored worse than single Tg mice. Animals were sacrificed two months after ischemia. The total brain volume was decreased by 6.5% and 5% and the ventricular volume was increased by 33.7% and 46.4% in single and double operated Tg mice, respectively comparing to sham animals. Unbiased stereological analysis demonstrated a 23% neuronal dropout in the CA1 sector of the cornu Ammonis after ischemia. Increased Abetaburden and plaque density was also observed in APP/PS1 animals which underwent ischemia comparing to sham operated ones. Overall, this data indicate that global ischemia exacerbate both neuronal and Abetarelated pathology in AD Tg animal models
— id: 97611, year: 2003, vol: 2003, page: Abstract No. 534.7, stat: Journal Article,

Inhibition of apolipoprotein E binding to amyloid - beta decreases fibril formation and deposition in vitro and in vivo
Sadowski, M.; Ji, Y.; Scholtzova, H.; Pankiewicz, J.; Sigurdsson, E. M.; Wisniewski, T.
2003 ;2003(5 Supplement 1):Abstract No. 666.6-118, Society for Neuroscience Abstract Viewer & Itinerary Planner
Deposition of amyloid-beta (Abeta) in form of the senile plaques and in vessel walls is a hallmark of Alzheimer's disease (AD). Apolipoprotein E (apoE) is known to act as a pathological chaperone by increasing the beta-sheet content of Abeta, promoting its fibrillization, toxicity, and deposition in the brain. ApoE binds to residues 12-28 of Abeta. We report in vitro and in vivo data on the blocking of the apoE/Abeta interaction by a synthetic peptide homologues to residues 12-28 of Abeta. To eliminate any residual toxicity and fibrillogenic potential the peptide sequence was altered by replacing a valine in position 18 by a proline (Abeta12-28P). On ELISA Abeta12-28P demonstrates high affinity binding to apoE and in competitive binding experiments inhibits the binding of apoE to Abeta42. Abeta12-28P also reduces the toxicity of Abeta in cell culture, as well as blocking the enhanced fibril formation of Abeta in the presence of apoE4, measured by the Thioflavin-T assay. The in vivo effect of Abeta12-28P was assessed in double transgenic (Tg) APP/PS1 AD mice which received 1mg of Abeta12-28P or placebo three times a week for four weeks. There was an approximately five fold reduction of the total and fibrillar Abeta in treated mice comparing to control (p<0.05). Also, Abeta40 and Abeta42 levels in the brain demonstrated a 40-60% reduction of both species in the total Abeta fraction and in the soluble Abeta fraction in treated mice comparing to controls. No significant titer of anti-Abeta antibodies in treated animals was detected, indicating that the effect of Abeta12-28P on Abeta deposition observed in vivo is not immune mediated. Overall, compounds blocking the interaction between Abeta and its pathological chaperones such as apoE (or alpha1anti-chymotrypsin, perlecan etc.) can be considered as an alternative approach for the treatment of beta-amyloidosis in AD
— id: 97615, year: 2003, vol: 2003, page: Abstract No. 666.6, stat: Journal Article,

Blocking apolipoprotein E/beta-amyloid interaction as a therapeutic approach for Alzheimer's disease
Sadowski, Marcin; Ji, Yong; Scholtzova, Henrieta; Sigurdsson, Einar M.; Wisniewski, Thomas
2003 ;60(5 Supplement 1):A68-118, Neurology
— id: 97613, year: 2003, vol: 60, page: A68, stat: Journal Article,

MRI approaches for the detection of prion disease pathology
Sadowski, Marcin; Tang, Cheuk Ying; Aguinaldo, Gilbert; Carp, Richard; Wadghiri, Youssef Zaim; Turnbull, Daniel H.; Wisniewski, Thomas
2003 ;60(5 Supplement 1):A250-118, Neurology
— id: 97614, year: 2003, vol: 60, page: A250, stat: Journal Article,

In vivo micro magnetic resonance imaging signal changes in scrapie infected mice
Sadowski, Marcin; Tang, Cheuk Ying; Aguinaldo, Juan Gilberto; Carp, Richard; Meeker, Harry C; Wisniewski, Thomas
2003 Jul 10;345(1):1-4, Neuroscience letters
Signal abnormalities on magnetic resonance imaging (MRI) T2-weighted images (T2WI) have been described in patients with Creutzfeldt-Jakob disease; however, the pathology underlying these findings remains to be fully described. We investigated the time-course of signal alterations in a murine model of prion disease using in vivo 9.4 Tesla micro magnetic resonance imaging (muMRI). The topography of muMRI signal changes was correlated with the accumulation of proteinase resistant PrP(Sc) in corresponding brain sections. Increased signal intensity on T2WI was observed in the septum and in the hippocampus of presymptomatic mice 120 days post infection (dpi). Mildly symptomatic animals (150 dpi) and animals with apparent neurological deficit (180 dpi) had a greater increase of signal intensity on T2WI in the septum and the hippocampus; in addition, abnormalities in the cortex and in the thalamus were found. Neuropathological evaluation demonstrated accumulation of PrP(Sc) and astrogliosis but only minimal or no spongiform changes in structures where abnormal signal was detected. These observations suggest that early pathological changes related to the accumulation of PrP(Sc) may be detectable in presymptomatic subjects using MRI systems with higher magnetic field strength
— id: 38796, year: 2003, vol: 345, page: 1, stat: Journal Article,

Immunological therapeutic and imaging approaches for prion disease
Sadowski, Marcin; Wisniewski, Thomas
2003 ;3(2):113-118, Current medicinal chemistry: Immunology, endocrine & metabolic agents
— id: 97612, year: 2003, vol: 3, page: 113, stat: Journal Article,

Mice expressing presenilin - 1 mutations demonstrate age - related neuronal loss
Scholtzova, H.; Pankiewicz, J.; Sadowski, M.; Li, Y. S.; Quartermain, D.; Wen, P. H.; Elder, G.; Duff, K.; Wisniewski, T.
2003 ;2003(5 Supplement 1):Abstract No. 729.8-118, Society for Neuroscience Abstract Viewer & Itinerary Planner
Presenilin 1 (PS1) mutations have been identified in many pedigrees with early-onset familial Alzheimer's disease (FAD). PS1 mutants are known to influence gamma-secretase action and increase amyloid-beta (Abeta) 1-42 production, but there is also evidence suggesting direct involvement of PS1 in the neuronal pathology of AD. Transgenic (Tg) mice expressing the M146L PS1 mutation, associated with FAD symptom onset in the forties, demonstrate no difference in the total number of neurons (fractionator method) in the CA1 sector of the cornu Ammonis comparing with wild type (wt) animals at two months of age. At the age of 9 months and 22 months PS1 M146L Tg mice demonstrated 20% and 29% neuronal dropout comparing to age-matched controls, respectively (p<0.05). Between 2 months and 22 months old wt animals did not show any significant neuronal loss; however, 22 month old M146L PS1 mice showed a 41% neuronal decline compared to 2 month old controls. PS1 M146L Tg animals also exhibited impaired performance of both learning and retention on the Morris water maze test (p<0.05), but not on locomotor testing comparing to wt mice. We have also analyzed another line of Tg mice expressing a P117L PS1 mutation associated with an onset of disease as early as 23 years. These mice at the age of 6 months demonstrate a 17.9% reduction in the total number of CA1 neurons comparing to wt mice and a 26.5% reduction comparing to mice expressing the wt form of human PS1 (p<0.05). Overall, this data suggest that PS1 mutations are directly involved in neuronal pathology which is age-dependant. This process is unrelated to Abeta deposition since PS1 Tg mice do not develop amyloid plaques
— id: 97616, year: 2003, vol: 2003, page: Abstract No. 729.8, 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,

Ex - vivo magnetic resonance imaging of beta - amyloid plaques in transgenic AD mice
Tang, C.; Hajianpour, A.; Aguinaldo, G.; Ho, L.; Pasinetti, G.; Hof, P. R.; Perl, D. P.; Sadowski, M.; Wisniewski, T.
2003 ;2003(5 Supplement 1):Abstract No. 862.3-118, Society for Neuroscience Abstract Viewer & Itinerary Planner
According to the amyloid hypothesis, it is the progressive accumulation of beta-amyloid that leads to a cascade of neurodegenerative processes in Alzheimer's disease (AD). Thus, current strategies for diagnosis and treatment evaluation rely on the ability to accurately quantify beta-amyloid burden. It has previously been shown that beta-amyloid plaques can be imaged using Magnetic Resonance Microscopy (MRM) at 40mum isotropic resolution in ex vivo human samples of the hippocampus. Transgenic (Tg) mice have been generated for research as beta-amyloidosis models. Plaque sizes range can from 5mum to 200mum, with an average diameter of approximately 25mum. In the present study, we used high resolution MRM to explore the feasibility of visualizing beta-amyloid plaque deposits in the brain of Tg2576 mice carrying the Swedish mutation of APP. We obtained T2 weighted 3D whole brain MRM data at 20mum and 25mum isotropic resolution. MRM images were compared with histological data to confirm that the signal seen on MRM corresponded to actual beta-amyloid plaque deposits. We conclude that MRM is a practical and useful assay for imaging beta-amyloid plaques with diameters as small as 20mum. These results will aid in the interpretation of MRI data gathered from in-vivo scans of mice, including scans wherein contrast agents are employed. This MRI technique can be easily applied to whole brain plaque quantification studies and for the purpose of studying treatment strategies using mouse models of AD, and may further be extended to in vivo studies tracking amyloid deposit formation and maturation throughout the animals life span
— id: 97617, year: 2003, vol: 2003, page: Abstract No. 862.3, stat: Journal Article,

Detection of Alzheimer's amyloid in transgenic mice using magnetic resonance microimaging
Wadghiri, Youssef Zaim; Sigurdsson, Einar M; Sadowski, Marcin; Elliott, James I; Li, Yongsheng; Scholtzova, Henrieta; Tang, Cheuk Ying; Aguinaldo, Gilbert; Pappolla, Miguel; Duff, Karen; Wisniewski, Thomas; Turnbull, Daniel H
2003 Aug;50(2):293-302, Magnetic resonance in medicine
The presence of amyloid-beta (Abeta) plaques in the brain is a hallmark pathological feature of Alzheimer's disease (AD). Transgenic mice overexpressing mutant amyloid precursor protein (APP), or both mutant APP and presenilin-1 (APP/PS1), develop Abeta plaques similar to those in AD patients, and have been proposed as animal models in which to test experimental therapeutic approaches for the clearance of Abeta. However, at present there is no in vivo whole-brain imaging method to detect Abeta plaques in mice or men. A novel method is presented to detect Abeta plaques in the brains of transgenic mice by magnetic resonance microimaging (muMRI). This method uses Abeta1-40 peptide, known for its high binding affinity to Abeta, magnetically labeled with either gadolinium (Gd) or monocrystalline iron oxide nanoparticles (MION). Intraarterial injection of magnetically labeled Abeta1-40, with mannitol to transiently open the blood-brain barrier (BBB), enabled the detection of many Abeta plaques. Furthermore, the numerical density of Abeta plaques detected by muMRI and by immunohistochemistry showed excellent correlation. This approach provides an in vivo method to detect Abeta in AD transgenic mice, and suggests that diagnostic MRI methods to detect Abeta in AD patients may ultimately be feasible
— id: 38795, year: 2003, vol: 50, page: 293, stat: Journal Article,

Redistribution of minibrain kinase in aging and neurodegeneration
Wegiel, J; Kuchna, I; Nowicki, K; Dowiat, K; Reisberg, B; deLeon, M; Wisniewski, T; Chen-Hwang, M; Hwang, Y
2003 MAY ;62(5):546-546, Journal of neuropathology & experimental neurology
— id: 38568, year: 2003, vol: 62, page: 546, stat: Journal Article,

The neuropathology of Alzheimer dementia
Weigel J; Wisniewski T; Reisberg B; Silverman W
Dementia : presentations, differential diagnosis, and nosology Baltimore MD : Johns Hopkins Press, 2003,
— id: 4978, year: 2003, vol: , page: 89, stat: Chapter,

in vivo magnetic resonance imaging of amyloid plaques in AD model mice
Wisniewski, T.; Sigurdsson, E. M.; Wadghiri, Y. Z.; Sadowski, M.; Scholtzova, H.; Tang, C. Y.; Aguilnaldo, G.; Duff, K.; Turnbull, D. H.
2003 ;2003(2):Abstract No. 203.7-302, Society for Neuroscience Abstract Viewer & Itinerary Planner
Amyloid deposition in Alzheimer's disease (AD) occurs many years before cognitive impairment. Brain imaging techniques targeting plaques will have an important diagnostic value and may help in identifying individuals in preclinical stages of AD. Magnetic resonance imaging (MRI) has a much higher resolution than positron enhanced tomography (PET) imaging and, therefore, is a more sensitive method to detect amyloid plaques. In our initial proof-of-concept studies (Magnetic Resonance in Medicine, in press), we utilized Abeta1-40 peptide, labeled with gadolinium or monocrystalline iron oxide nanoparticles (MION). When either of these ligands is injected in vivo systemically with mannitol to transiently open the blood-brain-barrier, we are able to image ex vivo the majority of Abeta plaques in Tg mice. Using Gd labeled Abeta1-40 and in vivo muMRI, we can also detect a substantial percentage of amyloid lesions. There is a high correlation between the numerical density of Abeta plaques detected by muMRI and by immunohistochemistry. Clinical use of Abeta1-40 is not feasible because it may add to the plaque burden. As a safer approach, we are using gadolinium labeled K6Abeta1-30, a non-toxic Abeta derivative with low propensity to form beta-sheet, while maintaining high affinity for Abeta. Our initial findings indicate that this compound has a similar effect as gadolinium labeled Abeta1-40 in allowing in vivo detection of amyloid plaques in Tg mice. We are currently exploring various ways to enhance the uptake of this compound into the brain. This approach may lead to a diagnostic MRI method to detect Abetaplaques in AD patients
— id: 97618, year: 2003, vol: 2003, page: Abstract No. 203.7, stat: Journal Article,

Immunization approaches for the treatment of prion disease
Wisniewski, Thomas; Sy, Man-Sun; Sadowski, Marcin; Kascsak, Richard J.; Kascsak, Regina; Carp, Richard; Goni, Fernando; Sigurdsson, Einar
2003 ;60(5 Supplement 1):A250-302, Neurology
— id: 97619, year: 2003, vol: 60, page: A250, stat: Journal Article,

Mapping the antigenicity of copper-treated cellular prion protein with the scrapie isoform
Wong, BS; Li, R; Sassoon, J; Kang, SC; Liu, T; Pan, T; Greenspan, NS; Wisniewski, T; Brown, DR; Sy, MS
2003 JUN ;60(6):1224-1234, Cellular & molecular life sciences: CMLS
When recombinant and cellular prion protein (PrPC) binds copper, it acquires properties resembling the scrapie isoform (PrPSc), namely protease resistance, detergent insolubility and increased Beta sheet content. However, whether the conformations of PrPC induced by copper and PrPSc are similar has not been studied in great detail. Here, we use a panel of seven monoclonal antibodies to decipher the epitopes on full-length mouse PrPC that are affected by exogenous copper, and to compare the antigenicity of the copper-treated full-length PrPC with the full-length PrPSc present in scrapie-infected mouse brains. In the presence of copper, we found that epitopes along residues 115-130 and 153-165 become more accessible on PrPC. These regions correspond to the two Beta sheet strands in recombinant PrP and they were proposed to be important for prion conversion. However, when we compared the antibody-binding patterns between full-length PrPC with full-length PrPSc and between copper-treated full-length PrPC with full-length PrPSc, antibody binding to residues 143-155 and 175-185 was consistently increased on PrPSc. Collectively, our results suggest that copper-treated full-length PrPC does not resemble full-length PrPSc, despite acquiring PrPSc-like properties. In addition, since each full-length protein reacts distinctively to some of the antibodies, this binding pattern could discriminate between PrPC and PrPSc
— id: 37096, year: 2003, vol: 60, page: 1224, stat: Journal Article,

Prion protein ubiquitination and proteasomal dysfunction in scrapie infection
Wong, BS; Whiteman, M; Sassoon, J; Kang, SC; Li, R; Pan, T; Smith, MA; Perry, G; Brown, DR; Wisniewski, T; Sy, MS
2003 DEC ;87(2):92-92, Journal of neurochemistry
— id: 98218, year: 2003, vol: 87, page: 92, stat: Journal Article,

Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment
de Leon, M J; Segal, S; Tarshish, C Y; DeSanti, S; Zinkowski, R; Mehta, P D; Convit, A; Caraos, C; Rusinek, H; Tsui, W; Saint Louis, L A; DeBernardis, J; Kerkman, D; Qadri, F; Gary, A; Lesbre, P; Wisniewski, T; Poirier, J; Davies, P
2002 Nov 29;333(3):183-186, Neuroscience letters
Cross-sectional cerebrospinal fluid (CSF) levels of tau and amyloid (A) beta (beta) are of diagnostic importance for Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, most longitudinal studies of tau fail to demonstrate progression. Because predominantly brain-derived proteins such as tau, have higher ventricle to lumbar ratios, we hypothesized that adjusting for the ventricular enlargement of AD would correct for the dilution of tau, and improve detection of longitudinal change. Abeta which is not exclusively brain derived, shows a ratio <1, and no benefit was expected from adjustment. In a 1 year longitudinal study of eight MCI and ten controls, we examined CSF levels of hyperphosphorylated (P) tau231, Abeta40, and Abeta42. In cross-section, MCI patients showed elevated Ptau231 and Abeta40 levels, and greater ventricular volumes. Longitudinally, only after adjusting for the ventricular volume and only for Ptau231, were increases seen in MCI. Further studies are warranted on mechanisms of tau clearance and on using imaging to interpret CSF studies
— id: 39372, year: 2002, vol: 333, page: 183, 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,

Rapid labeling of neuronal structures in post-mortem human brain by ballistic delivery of lipophilic dyes
Grutzendler, J; Gong, YD; Gan, WB; Wisniewski, T
2002 Jul-Aug;23(1):1762-, Neurobiology of aging
— id: 32435, year: 2002, vol: 23, page: 1762, stat: Journal Article,

Apolipoprotein E expression modulates neuronal spine density in an isotype specific manner in transgenic mice
Ji, Y; Gong, YD; Gan, WB; Wisniewski, T
2002 Jul-Aug;23(1):1472-, Neurobiology of aging
— id: 32426, year: 2002, vol: 23, page: 1472, stat: Journal Article,

Slower rates of Alzheimer's disease-related neuronal loss in the entorhinal cortex in Down's syndrome compared to sporadic Alzheimer's disease
Kuchna, I; Wegiel, J; Silverman, W; Pirttila, T; Visser, F; Wisniewski, T; Reisberg, B
2002 Jul-Aug;23(1):1763-, Neurobiology of aging
— id: 32436, year: 2002, vol: 23, page: 1763, 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,

Presenilin-1-dependent gamma-secretase cleavage of E-cadherin controls adherens junction disassembly
Marambaud, P; Shioi, J; Serban, G; Georgakopoulos, A; Sarner, S; Nagy, V; Baki, L; Wen, P; Efthimiopoulos, S; Wisniewski, T; Robakis, N
2002 Jul-Aug;23(1):802-, Neurobiology of aging
— id: 32418, year: 2002, vol: 23, page: 802, stat: Journal Article,

A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions
Marambaud, Philippe; Shioi, Junichi; Serban, Geo; Georgakopoulos, Anastasios; Sarner, Shula; Nagy, Vanja; Baki, Lia; Wen, Paul; Efthimiopoulos, Spiros; Shao, Zhiping; Wisniewski, Thomas; Robakis, Nikolaos K
2002 Apr 15;21(8):1948-1956, EMBO journal
E-cadherin controls a wide array of cellular behaviors including cell-cell adhesion, differentiation and tissue development. Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, controls a gamma-secretase-like cleavage of E-cadherin. This cleavage is stimulated by apoptosis or calcium influx and occurs between human E-cadherin residues Leu731 and Arg732 at the membrane-cytoplasm interface. The PS1/gamma-secretase system cleaves both the full-length E-cadherin and a transmembrane C-terminal fragment, derived from a metalloproteinase cleavage after the E-cadherin ectodomain residue Pro700. The PS1/gamma-secretase cleavage dissociates E-cadherins, beta-catenin and alpha-catenin from the cytoskeleton, thus promoting disassembly of the E-cadherin-catenin adhesion complex. Furthermore, this cleavage releases the cytoplasmic E-cadherin to the cytosol and increases the levels of soluble beta- and alpha-catenins. Thus, the PS1/gamma-secretase system stimulates disassembly of the E-cadherin- catenin complex and increases the cytosolic pool of beta-catenin, a key regulator of the Wnt signaling pathway
— id: 39675, year: 2002, vol: 21, page: 1948, stat: Journal Article,

Intraneuronal Abeta42 accumulation in Down syndrome brain
Mori, Chica; Spooner, Edward T; Wisniewsk, Krystyna E; Wisniewski, Thomas M; Yamaguch, Haruyasu; Saido, Takaom C; Tolan, Dean R; Selkoe, Dennis J; Lemere, Cynthia A
2002 Jun;9(2):88-102, Amyloid
Alzheimer's disease (AD) brains display A beta (Abeta) plaques, inflammatory changes and neurofibrillary tangles (NFTs). Converging evidence suggests a neuronal origin of Abeta. We performed a temporal study of intraneuronal Abeta accumulation in Down syndrome (DS) brains. Sections from temporal cortex of 70 DS cases aged 3 to 73 years were examined immunohistochemicallyf or immunoreactivity (IR) for the Abeta N-terminal, the Abeta40 C-terminus and the Abeta42 C-terminus. N-terminal antibodies did not detect intracellular Abeta. Abeta40 antibodies did not detect significant intracellular Abeta, but older cases showed Abeta40 IR in mature plaques. In contrast, Abeta42 antibodies revealed clear-cut intraneuronal IR. All Abeta42 antibodies tested showed strong intraneuronal Abeta42 IR in very young DS patients, especially in theyoungest cases studied (e.g., 3 or 4yr. old), but this IR declined as extracellular Abeta plaques gradually accumulated and matured. No inflammatory changes were associated with intraneuronal Abeta. We also studied the temporal development of gliosis and NFT formation, revealing that in DS temporal cortex, inflammation and NFT follow Abeta deposition. We conclude that Abeta42 accumulates intracellularly prior to extracellular Abeta deposition in Down syndrome, and that subsequent maturation of extracellular Abeta deposits elicits inflammatory responses andprecedes NFTs
— id: 32919, year: 2002, vol: 9, page: 88, stat: Journal Article,

Molecular targeting of Alzheimer's amyloid plaques for contrast-enhanced magnetic resonance imaging
Poduslo, JF; Wengenack, T; Curran, GV; Macura, S; Borowski, B; Jack, C; Wisniewski, T; Sigurdsson, E
2002 ;23(1):1550-329, Neurobiology of aging
— id: 97596, year: 2002, vol: 23, page: 1550, stat: Journal Article,

Molecular targeting of Alzheimer's amyloid plaques for contrast-enhanced magnetic resonance imaging
Poduslo, JF; Wengenack, TM; Curran, GL; Wisniewski, T; Sigurdsson, EM; Macura, SI; Borowski, BJ; Jack, CR
2002 Jun;81(7):61-61, Journal of neurochemistry
— id: 32368, year: 2002, vol: 81, page: 61, stat: Journal Article,

Molecular targeting of Alzheimer's amyloid plaques for contrast-enhanced magnetic resonance imaging
Poduslo, Joseph F; Wengenack, Thomas M; Curran, Geoffry L; Wisniewski, Thomas; Sigurdsson, Einar M; Macura, Slobodon I; Borowski, Bret J; Jack, Clifford R Jr
2002 Nov;11(2):315-329, Neurobiology of disease
Smart molecular probes for both diagnostic and therapeutic purposes are expected to provide significant advances in clinical medicine and biomedical research. We describe such a probe that targets beta-amyloid plaques of Alzheimer's disease and is detectable by magnetic resonance imaging (MRI) because of contrast imparted by gadolinium labeling. Three properties essential for contrast enhancement of beta-amyloid plaques on MRI exist in this smart molecular probe, putrescine-gadolinium-amyloid-beta peptide: (1) transport across the blood-brain barrier following intravenous injection conferred by the polyamine moiety, (2) binding to plaques with molecular specificity by putrescine-amyloid-beta, and (3) magnetic resonance imaging contrast by gadolinium. MRI was performed on ex vivo tissue specimens at 7 T at a spatial resolution approximating plaque size (62.5 microm(3)), in order to prove the concept that the probe, when administered intravenously, can selectively enhance plaques. The plaque-to-background tissue contrast-to-noise ratio, which was precisely correlated with histologically stained plaques, was enhanced more than nine-fold in regions of cortex and hippocampus following intravenous administration of this probe in AD transgenic mice. Continuing engineering efforts to improve spatial resolution are underway in MRI, which may enable in vivo imaging at the resolution of individual plaques with this or similar contrast probes. This could enable early diagnosis and also provide a direct measure of the efficacy of anti-amyloid therapies currently being developed
— id: 62132, year: 2002, vol: 11, page: 315, 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,

Unique cleavage site of E-cadherin by presenilin-associated gamma-secretase
Shioi, J; Marambaud, P; Shao, ZP; Robakis, NK; Wisniewski, TM
2002 Jul-Aug;23(1):779-, Neurobiology of aging
— id: 32417, year: 2002, vol: 23, page: 779, 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,

In vivo detection of Alzheimer's amyloid by magnetic resonance imaging
Sigurdsson, EM; Wadghiri, YZ; Li, Q; Scholtzova, H; Tang, CY; Aguilnaldo, JG; Duff, K; Pappolla, M; Elliott, JI; Watanabe, M; Turnbull, DH; Wisniewski, T
2002 Jul-Aug;23(1):1307-, Neurobiology of aging
— id: 32425, year: 2002, vol: 23, page: 1307, stat: Journal Article,

Therapeutic effects of astrocytes expressing both tyrosine hydroxylase and brain-derived neurotrophic factor on a rat model of Parkinson's disease
Wang, Z H; Ji, Y; Shan, W; Zeng, B; Raksadawan, N; Pastores, G M; Wisniewski, T; Kolodny, E H
2002 ;113(3):629-640, Neuroscience
Tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF), expressed in normal astrocytes, were used in combination for the treatment of Parkinson's disease (PD) symptoms in a rat model. Normal neonatal rat astrocytes were co-transfected with a vector expressing BDNF (AAVBDNF) and a retroviral vector expressing TH (termed TH-BDNF-DA(+) cells), and then implanted into the striatum of PD rats induced by 6-hydroxydopamine. TH-BDNF-DA(+) cells compensated for a severe insufficiency of endogenous dopaminergic neurons in the PD rats, resulting in a significant improvement of PD symptoms. The decrease in the rotational rate of PD rats implanted with TH-BDNF-DA(+) cells was more marked than that in PD rats implanted with normal astrocytes expressing either TH or BDNF alone (termed TH(+) and BDNF(+) cells, P<0.01 and 0.001, respectively), and suggested a synergistic effect between TH and BDNF. In contrast, the rotational rate was not altered from the baseline in PD rats without treatment or implanted with parental rat astrocytes alone (P>0.05). BDNF protected the dopaminergic neurons from apoptosis induced by 6-hydroxydopamine, and significantly increased the long-term survival of TH-positive cells in the striatum.Our data indicate that the combined use of TH and BDNF has a synergistic therapeutic effect, and is more efficient for the treatment of PD than a single gene therapy using either TH or BDNF alone
— id: 39612, year: 2002, vol: 113, page: 629, stat: Journal Article,

Intraneuronal accumulation of N-terminally truncated amyloid beta
Wegiel, J; Kuchna, I; Miller, D; Mehta, P; Wegiel, J; Wisniewski, T; Reisberg, B; Silverman, W
2002 May;61(5):164-, Journal of neuropathology & experimental neurology
— id: 28188, year: 2002, vol: 61, page: 164, stat: Journal Article,

Vascular fibrosis and calcification in the hippocampus in aging, Alzheimer disease, and Down syndrome
Wegiel, J; Kuchna, I; Wisniewski, T; de Leon, M J; Reisberg, B; Pirttila, T; Kivimaki, T; Lehtimaki, T
2002 Apr;103(4):333-343, Acta neuropathologica
Study of the hippocampal formation of 82 subjects, including 25 control subjects from 33 to 83 years of age, 34 subjects with Alzheimer disease (AD) from 65 to 89 years of age, and 23 subjects with Down syndrome (DS) from 33 to 72 years of age, revealed hippocampal vasculopathy with fibrosis and calcification (VFC) in 40% of control, 59% of AD, and 4% of DS subjects. VFC starts in the precapillaries/capillaries in the molecular layer of the dentate gyrus (DG) and expands to the granule cell and polymorphic cell layer of the DG, and to the stratum lacunosum/molecular in the CA1 sector. Vasculopathy spreads from the tail to the body and, in a few cases, to the head of the hippocampal formation. Light and electron microscopy reveal thickening of the vascular wall with fibrosis, calcification, and enforcement of the astrocyte interface with vessels with anchorage densities associated with hemidesmosome-like structures. In moderately and severely affected cases, fragmentation and removal of calcified and occluded vessels result in local reduction of vascular network. In two AD subjects, severe vascular calcification extending from the tail to the head of the hippocampal formation was associated with loss of almost all neurons in the CA1 sector and in the subiculum proper, corresponding to hippocampal sclerosis. The topography of affected vessels and the patterns of neuronal loss reflect the middle hippocampal artery distribution with its precapillary/capillary network. The similar prevalence of vasculopathy in the AD group and in the age-matched control group, and the presence of hippocampal VFC in only one subject in the DS cohort, 96% of which is affected by Alzheimer-type pathology, oppose the link between AD and this form of vasculopathy. However, severe VFC affects the pattern of AD pathology locally by deletion of neurofibrillary degeneration and beta-amyloidosis in the CA1 sector, subiculum proper, and the molecular layer of the dentate gyrus. Hippocampal VFC appears to be a form of vascular pathology with a unique predilection for the middle hippocampal artery and corresponding capillary network, which results in patchy neuronal loss in moderately affected subjects and in almost total neuronal loss in the area of impaired blood supply in severely affected subjects. These observations suggest an etiologic link between hippocampal VFC and hippocampal sclerosis
— id: 34298, year: 2002, vol: 103, page: 333, stat: Journal Article,

Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice
Wen, Paul H; Shao, Xiang; Shao, Zhiping; Hof, Patrick R; Wisniewski, Thomas; Kelley, Kevin; Friedrich, Victor L Jr; Ho, Lap; Pasinetti, Giulio M; Shioi, Junichi; Robakis, Nikolaos K; Elder, Gregory A
2002 Jun;10(1):8-19, Neurobiology of disease
Mutations in the presenilin-1 (PS-1) gene are one cause of familial Alzheimer's disease (FAD). However, the functions of the PS-1 protein as well as how PS-1 mutations cause FAD are incompletely understood. Here we investigated if neuronal overexpression of wild-type or FAD mutant PS-1 in transgenic mice affects neurogenesis in the hippocampus of adult animals. We show that either a wild-type or an FAD mutant PS-1 transgene reduces the number of neural progenitors in the dentate gyrus. However, the wild-type, but not the FAD mutant PS-1 promoted the survival and differentiation of progenitors leading to more immature granule cell neurons being generated in PS-1 wild type expressing animals. These studies suggest that PS-1 plays a role in regulating neurogenesis in adult hippocampus and that FAD mutants may have deleterious properties independent of their effects on amyloid deposition
— id: 47187, year: 2002, vol: 10, page: 8, stat: Journal Article,

Prion related diseases
Wisniewski T; Sigurdsson E
2002;:- [Web site], 2002-, Emedicine
— id: 150918, year: 2002, vol: , page: , stat: Web Site,

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,

Therapeutics in Alzheimer's and prion diseases
Wisniewski, T; Brown, D R; Sigurdsson, E M
2002 Aug;30(4):574-578, Transactions (Biochemical Society (Great Britain))
There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease, amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid-beta peptide (sA beta) to A beta plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to the disease-associated form, PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. A number of different approaches under current development include drugs which affect the processing of the precursor proteins drugs the clearance of the amyloidogenic protein, and which inhibit or prevent the conformation change and immunological approaches. Particularly interesting are compounds termed 'beta-sheet breakers' that directly target the abnormal conformational change both for A beta- and PrP(Sc)-related deposits. In addition, immune system activation can serve as beta-sheet breakers and/or to increase the clearance of the disease-associated proteins. These conformation-based approaches appear to hold the best promise for therapies for this devastating group of disorders
— id: 32922, year: 2002, vol: 30, page: 574, 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,

Immunization treatment approaches in Alzheimer's and prion diseases
Wisniewski, Thomas; Sigurdsson, Einar M
2002 Sep;2(5):400-404, Current neurology & neuroscience reports
There is growing realization that many neurodegenerative conditions have the same underlying pathogenetic mechanism: a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease (AD), amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid beta (sAbeta) to Abeta plaques, whereas in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. Different approaches under development include drugs that affect the processing of the precursor proteins, enhance clearance of the amyloidogenic protein, and inhibit or prevent the conformation change. Particularly interesting are recent studies of immune system activation, which appear to increase the clearance of the disease-associated protein. These immunologically based approaches are highly effective in animal models of these disorders, and in these model systems are associated with no obvious side effects. In transgenic mice with AD-related pathology, immunization has also been shown to prevent age-related cognitive impairment. However, the first clinical trial of this approach in AD patients was associated with unacceptable toxicity. These immune-based treatment approaches have great potential as rational therapies for this devastating group of disorders, but additional development is needed before they can be safely applied to humans
— id: 32923, year: 2002, vol: 2, page: 400, stat: Journal Article,

Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie
Aucouturier P; Geissmann F; Damotte D; Saborio GP; Meeker HC; Kascsak R; Kascsak R; Carp RI; Wisniewski T
2001 Sep;108(5):703-708, Journal of clinical investigation
Transmissible spongiform encephalopathies display long incubation periods at the beginning of which the titer of infectious agents (prions) increases in peripheral lymphoid organs. This 'replication' leads to a progressive invasion of the CNS. Follicular dendritic cells appear to support prion replication in lymphoid follicles. However, the subsequent steps of neuroinvasion remain obscure. CD11c(+) dendritic cells, an unrelated cell type, are candidate vectors for prion propagation. We found a high infectivity titer in splenic dendritic cells from prion-infected mice, suggesting that dendritic cells carry infection. To test this hypothesis, we injected RAG-1(0/0) mice intravenously with live spleen cell subsets from scrapie-infected donors. Injection of infected dendritic cells induced scrapie without accumulation of prions in the spleen. These results suggest that CD11c(+) dendritic cells can propagate prions from the periphery to the CNS in the absence of any additional lymphoid element
— id: 23495, year: 2001, vol: 108, page: 703, stat: Journal Article,

Infected splenic dendritic cells are sufficient for scrapie neuroinvasion in RAG-1(0/0) mice
Aucouturier, P; Geissmann, F; Carnaud, C; Kascsak, R; Wisniewski, T; Carp, RI
2001 MAR 8 ;15(5):A1011-A1011, FASEB journal
— id: 55091, year: 2001, vol: 15, page: A1011, stat: Journal Article,

Neuronal degeneration and loss in nigro-striatal system in Alzheimer disease, Down syndrome, and Parkinson disease
Badmaev, E; Wegiel, J; Nowicki, K; Kuchna, I; Tarnawski, M; Wrzolek, M; Pirttila, T; Kivimaki, T; Lehtimaki, T; Reisberg, B; de Leon, M; Wisniewski, T; Silverman, W
2001 MAY ;60(5):545-545, Journal of neuropathology & experimental neurology
— id: 55072, year: 2001, vol: 60, page: 545, stat: Journal Article,

Alzheimer's disease presenilin-1 expression modulates the assembly of neurofilaments
Dowjat WK; Wisniewski H; Wisniewski T
2001 ;103(1):1-8, Neuroscience
Mutations in presenilin-1 gene are responsible for the majority of early-onset familial Alzheimer's disease cases. The function of this protein and the mechanism underlying the pathogenicity of its mutations are still unclear. To elucidate the role of presenilin-1 in the Alzheimer's disease pathology, we tested two such mutations (P117L and M146L) for their effect in stably transfected mouse neuroblastoma cell lines. Over-expression of the wild-type presenilin-1 gene induced formation of a well-extended, orderly organized network consisting of neurofilaments assembled from the L and H subunits, while in cells with the mutant gene this network was markedly reduced to short filaments concentrated in structures resembling cups. Cells expressing the mutant gene displayed altered processing of the transgene protein and neurofilament-H, suggesting that presenilin-1 is the mediator of changes targeted at neurofilaments. The two different mutations produced similar alterations, implying that this is a common pathogenic mechanism. Presenilin-1, neurofilament-H and tau proteins showed co-localization as evidenced by confocal microscopy, suggesting a possible physiological connection between these three proteins. Presenilin-1 appears to influence assembly of the H subunit into neurofilaments and the subsequent formation of new neurites. Mutations impair this function of presenilin-1, resulting in inhibition of neurite outgrowth. That presenilin-1 influences the assembly of neurofilaments may represent a novel pathway through which presenilin-1 mutations are involved in Alzheimer's disease pathology. In this hypothesis, presenilin-1 mutations will be associated with aberrant sprouting leading to synaptic loss, a key neuropathological feature of Alzheimer's disease
— id: 23494, year: 2001, vol: 103, page: 1, stat: Journal Article,

In vivo detection of neuropathology in an animal model of Alzheimer's disease by magnetic resonance imaging
Helpern, J. A.; Wisniewski, T.; Duff, K.; Dyakin, V.; de Leon, M.; Ardekani, B.; Wolf, O.; Branch, C.; O'Shea, J.; Wegiel, J.; Nixon, R. A.
2001 ;27(1):1217-343, Abstracts (Society for Neuroscience)
The cerebral deposition of amyloid beta-peptide, a central event in Alzheimer's disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Non-invasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. Here, we demonstrate the ability of high field strength MRI to detect regional brain volume reductions and ventricular enlargement in the PS-APP transgenic mouse model of AD more sensitively than histopathologic analysis by unbiased stereology. Moreover, the transverse relaxation time T2, an intrinsic MR parameter thought to reflect impaired cell physiology, was altered substantially in cortical regions containing beta-amyloid but only slightly in cerebellum, which contains little beta-amyloid. MR measures were also minimally altered in mice expressing mutant presenilin-1, which do not deposit beta-amyloid, supporting the view that the MR abnormalities in PS-APP mice are partly related to amyloid beta-peptide deposition. These results set the stage for MRI to aid in the early diagnosis of AD and the evaluation of potential therapies in transgenic animal models and in patients
— id: 97624, year: 2001, vol: 27, page: 1217, stat: Journal Article,

Introduction
Iqbal, Khalid; Wisniewski, Thomas
2001 ;3(1):3-3 Apr, Journal of Alzheimer's Disease
It is truly a great pleasure to have this special issue of the Journal of Alzheimer's Disease in the memory of Henry M. Wisniewski, who was one of the most well-known scientists in the field of Alzheimer's disease and animal models. We are very grateful that so many of Henry Wisnewski's colleagues, who are all accomplished Alzheimer disease researchers, have written articles for this memorial issue.
— id: 68944, year: 2001, vol: 3, page: 3, stat: Journal Article,

Amyloid beta40/42 clearance across the blood-brain barrier following intra-ventricular injections in wild-type, apoE knock-out and human apoE3 or E4 expressing transgenic mice
Ji Y; Permanne B; Sigurdsson EM; Holtzman DM; Wisniewski T
2001 Feb;3(1):23-30, Journal of Alzheimer's Disease
An important event in the pathogenesis of Alzheimer's disease (AD) is the deposition of the amyloid beta (Abeta)1-40 and 1-42 peptides in a fibrillar form, with Abeta42 typically having a greater propensity to undergo this conformational change. A major risk factor for late-onset AD is the inheritance of the apolipoprotein E (apoE) 4 allele [3,14,31]. We previously proposed that apoE may function as a 'pathological chaperone' in the pathogenesis of AD (i.e. modulate the structure of Abeta, promoting or stabilizing a beta-sheet conformation), prior to the discovery of this linkage [7,40,41,42]. Data from apoE knockout / AbetaPP^(V717F) mice, has shown that the presence of apoE is necessary for cerebral amyloid formation [1,2], consistent with our hypothesis. However, in betaPP^(V717F) mice expressing human apoE3 or E4 early Abeta deposition at 9 months is suppressed, but by 15 months both human apoE expressing mice had significant fibrillar Abeta deposits with the apoE4 expressing mice having a 10 fold greater amyloid burden [8,9]. This and other data has suggested that apoE, in addition to having a facilitating role in fibril formation, may also influence clearance of Abeta peptides. In order to address if apoE affects the clearance of Abeta peptides across the blood-brain barrier (BBB) and whether there are differences in the clearance of Abeta40 versus Abeta42, we performed stereotactic, intra-ventricular micro-injections of Abeta40, Abeta42 or control peptides in wild-type, apoE knock-out (KO) or human apoE3 or apoE4 expressing transgenic mice. We found that consistent with other studies [5], Abeta40 is rapidly cleared from the brain across the BBB; however, Abeta42 is cleared much less effectively. This clearance of exogenous Abeta peptides across the BBB does not appear to be affected by apoE expression. This data suggests that Abeta42 production may favor amyloid deposition due to a reduced clearance across the BBB, compared to Abeta40. In addition, our experiments support a role of apoE as a pathological chaperone, and do not suggest an isotype specific role of apoE in exogenous Abeta peptide clearance from the CSF across the BBB
— id: 32921, year: 2001, vol: 3, page: 23, stat: Journal Article,

[Familial Alzheimer's disease connected with mutation in presenilin gene 1 (P117L)]
Kulczycki, J; Bertrand, E; Lojkowska, W; Dowjat, W; Wisniewski, T; Lyczywek-Zwierz, M
2001 Mar-Apr;35(2):213-224, Neurologia i neurochirurgia polska
We describe a Polish family with Alzheimer's disease in some of its members. Two sisters were observed and examined--also neuropathologically in the Institute of Psychiatry and Neurology in Warsaw. The disease onset was in our patients at 32 and 33 years. The first symptoms were memory loss and disorientation. Later on myoclonus and extrapyramidal stiffness were noted in both cases. Neurovisualizing examinations performed in both sisters showed diffuse brain atrophy. The symptoms increased rapidly and in short time (several months) the patients became mute and bedbound. They died at age 35 and 37 years. We were informed that the father of the patients suffered from very similar illness and died at age of 37 years and their older brother had the some symptoms and died at the age of 28 years. Post-mortem brain examination disclosed in the both hospitalized cases diffuse atrophy of the cerebral hemispheres, particularly severe in the temporal lobes. Microscopically senile plaques of various types were found in the cortex. The density of the plaques was very high but Alzheimer's fibrillary degeneration was found occasionally only. The amyloid burden in cortex of the examined brains, estimated as the measure of parenchymal amyloidosis beta, was two to six-fold higher in most areas compared with changes in sporadic AD and Down-syndrome cases. DNA was isolated from blood and tissue of both cases and from blood of their 8 children as well. In both patients mutation in presenilin 1 (PS1) gene of Prol 117 Leu was found and it was discovered that 4 persons of their progeniture were carriers of this mutation. The described mutation causes one of the earliest so far reported onset and death in FAD kindreds. Presenilin isolated from both cases and transfected into cultures of murine neuroblastoma and human kidneys provoked production of beta amyloid with increased A-beta 42/40 ratio
— id: 97589, year: 2001, vol: 35, page: 213, 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,

Effect of the presenilin 1 P117L FAD linked mutation on hippocampal morphology transgenic mice
Sadowski, M; Wen, PH; Elder, GA; Robakis, NK; Wisniewski, T
2001 MAY ;60(5):543-543, Journal of neuropathology & experimental neurology
— id: 55071, year: 2001, vol: 60, page: 543, stat: Journal Article,

Apolipoprotein E mediated uptake of amyloid by astrocytes in vitro
Shao, CY; Ji, Y; Wisniewski, T
2001 MAY ;60(5):505-505, Journal of neuropathology & experimental neurology
— id: 55066, year: 2001, vol: 60, page: 505, 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,

Fibrillar amyloid-beta affects neurofibrillary changes but only in neurons already involved in neurofibrillary degeneration
Wegiel J; Bobinski M; Tarnawski M; Dziewiatkowski J; Popovitch E; Miller DC; Wisniewski T; Golomb J; de Leon MJ; Reisberg B
2001 Jun;101(6):585-590, Acta neuropathologica
The aim of this study of the cerebral cortex of 8 non-demented elderly subjects and of 17 subjects in the severe stage of Alzheimer's disease (AD) (Global Deterioration Scale stage 7/Functional Assessment Staging procedure stage 7a-f) was to examine the relationships between amyloid-beta (Abeta) deposits and neurofibrillary degeneration. The study shows that neuronal processes with neurofibrillary changes are detectable in only a minority of fibrillar plaques: from 31% to 49% of fibrillar plaques within frontal, temporal, parietal, limbic, occipital, and insular cortices. The correlations observed between the numerical densities of neurons with neurofibrillary tangles (NFTs) and the densities of Thioflavin-S-positive fibrillar plaques with neurofibrillary changes (r=0.61; P<0.01) indicate that neurofibrillary pathology in neocortical plaques reflects the topography and rate of neurofibrillary changes in neocortical neurons. The accumulation of abnormally phosphorylated tau in only some plaques indicates that fibrillar Abeta enhances paired helical filament accumulation locally only in dystrophic neurites already involved in neurofibrillary degeneration. The lack of correlation between the number of neurons with neurofibrillary changes and the number of all Thioflavin-S-positive fibrillar plaques (with and without neurofibrillary changes) suggests that beta-amyloidosis does not contribute to initiation of neurofibrillary degeneration in neurons
— id: 34299, year: 2001, vol: 101, page: 585, stat: Journal Article,

Henry M. Wisniewski M.D. Ph.D
Wisniewski T
2001 Feb;3(1):7-22, Journal of Alzheimer's Disease
— id: 39452, year: 2001, vol: 3, page: 7, stat: Journal Article,

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,

Prion diseases and the immune system
Aucouturier P; Carp RI; Carnaud C; Wisniewski T
2000 Aug;96(2):79-85, Clinical immunology
Transmissible spongiform encephalopathies are caused by unusual infectious agents that are purported to contain a single type of macromolecule, a modified host glycoprotein. The term prion has been applied to this group of agents. Surprisingly, the immune system appears to behave as a Trojan's horse rather than a protective fortification during prion infections. Because prions seem to be essentially composed of a protein, PrP(Sc), identical in sequence to a host encoded protein, PrP(C), the specific immune system displays a natural tolerance. However, lymphoid organs are strongly implicated in the preclinical stages of the disease. Certain immunodeficient animals are resistant to prions after peripheral inoculation. In normal subjects, cells of the immune system support the replication of prions and/or allow neuroinvasion. A better understanding of these aspects of prion diseases could lead to immunomanipulation strategies aimed at preventing the spread of infectious agents to the central nervous system.
— id: 11590, year: 2000, vol: 96, page: 79, stat: Journal Article,

Sodium dodecyl sulfate-resistant complexes of Alzheimer's amyloid beta-peptide with the N-terminal, receptor binding domain of apolipoprotein E
Golabek AA; Kida E; Walus M; Perez C; Wisniewski T; Soto C
2000 Aug;79(2):1008-1015, Biophysical journal
Immunocytochemical, biochemical, and molecular genetic studies indicate that apolipoprotein E (apoE) plays an important role in the process of amyloidogenesis-beta. However, there is still no clear translation of these data into the pathogenesis of amyloidosis-beta. Previous studies demonstrated sodium dodecyl sulfate (SDS)-resistant binding of apoE to the main component of Alzheimer's amyloid-A beta and modulation of A beta aggregation by apoE in vitro. To more closely characterize apoE-A beta interactions, we have studied the binding of thrombolytic fragments of apoE3 to A beta in vitro by using SDS-polyacrylamide gel electrophoresis and intrinsic fluorescence quenching. Here we demonstrate that SDS-resistant binding of A beta is mediated by the receptor-binding, N-terminal domain of apoE3. Under native conditions, both the N- and C-terminal domains of apoE3 bind A beta; however, the former does so with higher affinity. We propose that the modulation of A beta binding to the N-terminal domain of apoE is a potential therapeutic target for the treatment of amyloidosis-beta
— id: 34320, year: 2000, vol: 79, page: 1008, stat: Journal Article,

On the biological activity of vitamin E
Kayden, H J; Wisniewski, T
2000 Jul;72(1):201-203, American journal of clinical nutrition
— id: 101158, year: 2000, vol: 72, page: 201, stat: Journal Article,

In vivo A beta related neurotoxicity is dependent on the expression of apolipoprotein E
Shao, CY; Ji, Y; Mackey, B; Holtzman, DM; Wisniewski, T
2000 MAY ;59(5):425-425, Journal of neuropathology & experimental neurology
— id: 54611, year: 2000, vol: 59, page: 425, 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,

Temporal accrual of complement proteins in amyloid plaques in Down's syndrome with Alzheimer's disease
Stoltzner SE; Grenfell TJ; Mori C; Wisniewski KE; Wisniewski TM; Selkoe DJ; Lemere CA
2000 Feb;156(2):489-499, American journal of pathology
The complement system constitutes a series of enzymatic steps involved in the inflammatory response and is activated in Alzheimer's disease (AD). Using Down's syndrome (DS) brains as a temporal model for the progression of AD, we examined components of the complement cascade and their relationship to other principal events in AD pathology: Abeta42 deposition, neuritic changes, neurofibrillary tangles (NFTs), and gliosis (reactive astrocytes, activated microglia). Adjacent sections of frontal cortex from 24 DS subjects ranging in age from 12 to 73 years were immunohistochemically examined for immunoreactivity (IR) of classical complement proteins (Clq and C3), markers indicating activation of complement (C4d and C5b-9), the complement inhibitor apolipoprotein J (apo J), and markers of AD neuropathology. Abeta42-labeled diffuse plaques were first detected in a 12-year-old DS subject and were not labeled by any of the complement antibodies. Colocalization of Abeta42 with Clq, C3, C4d, and/or apo J was first detected in compacted plaques in the brain of a 15-year-old DS patient with features of mature AD pathology, such as reactive astrocytes, activated microglia, dystrophic neurites, and a few NFTs. IR for C4d and C5b-9 (membrane attack complex, MAC) was observed in small numbers of plaque-associated dystrophic neurites and in focal regions of pyramidal neurons in this 15-year-old. The only other young (</=30 years) DS brain to show extensive complement IR was that of a 29-year-old DS subject who also displayed the full range of AD neuropathological features. All middle-aged and old DS brains showed IR for Clq and C3, primarily in compacted plaques. In these cases, C4d IR was found in a subset of Abeta42 plaques and, along with C5b-9 IR, was localized to dystrophic neurites in a subset of neuritic plaques, neurons, and some NFTs. Our data suggest that in AD and DS, the classical complement cascade is activated after compaction of Abeta42 deposits and, in some instances, can progress to the local neuronal expression of the MAC as a response to Abeta plaque maturation
— id: 32243, year: 2000, vol: 156, page: 489, stat: Journal Article,

Shift from fibrillar to nonfibrillar A beta deposits in the neocortex of subjects with Alzheimer disease
Wegiel, J; Bobinski, M; Tarnawski, M; Popovitch, E; Lach, B; Reisberg, B; Miller, DC; Wisniewski, T; de Leon, MJ
2000 MAY ;59(5):421-421, Journal of neuropathology & experimental neurology
— id: 54608, year: 2000, vol: 59, page: 421, 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,

Abtracts from XI Conference of Polish Association of Neuropathologists, Warszawa, May 13-15, 1999
Adamczewska-Goncerzewicz, Z; Biczysko, W; Dorszczewska, J; Marszalek, M; Florek, E; Michalak, S; Bertand, E; Kulczycki, J; Wisniewski, T; Wegiel, J; Lewandowska, E; Lojkowska, W; Dymecki, J
1999 ;37(4):293-307, Folia neuropathologica
— id: 97625, year: 1999, vol: 37, page: 293, 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,

Familial Alzheimer's disease with an usually early onset and severity of disease
Bertrand, E.; Kulczycki, J.; Wisniewski, Th.; Wegiel, J.; Lewandowska, E.; Lojkowska, W.; Dymecki, J.
1999 ;435(3):374-307, Virchows archive
— id: 97626, year: 1999, vol: 435, page: 374, stat: Journal Article,

Localization of alpha-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders
Copp RP; Wisniewski T; Hentati F; Larnaout A; Ben Hamida M; Kayden HJ
1999 Mar 20;822(1-2):80-87, Brain research
Vitamin E (alpha-tocopherol) is an essential nutrient and an important antioxidant. Its plasma levels are dependent upon oral intake, absorption and transfer of the vitamin to a circulating lipoprotein. The latter step is controlled by alpha-tocopherol transfer protein (alpha-TTP), which is a 278 amino acid protein encoded on chromosome 8, known to be synthesized in the liver. Mutations in alpha-TTP are associated with a neurological syndrome of spinocerebellar ataxia, called ataxia with vitamin E deficiency (AVED). Earlier studies suggested that alpha-TTP is found only in the liver. In order to establish whether alpha-TTP is expressed in the human brain, and what relationship this has to AVED, we studied immunohistochemically the presence of alpha-TTP in the brains of a patient with AVED, normal subjects, and patients with Alzheimer's disease (AD), Down's syndrome (DS), cholestatic liver disease (CLD) and abetalipoproteinemia (ABL). The neuropathology of both AD and DS is thought to be related in part to oxidative stress. The diseases of AVED, of cholestatic liver disease, and of abetalipoproteinemia are thought to be due to lack of circulating tocopherol, leading to inadequate protection against oxidative damage. We demonstrate the presence of alpha-TTP in cerebellar Purkinje cells in patients having vitamin E deficiency states or diseases associated with oxidative stress.
— id: 6064, year: 1999, vol: 822, page: 80, stat: Journal Article,

Inhibition of neurite outgrowth by familial Alzheimer's disease-linked presenilin-1 mutations
Dowjat WK; Wisniewski T; Efthimiopoulos S; Wisniewski HM
1999 May 28;267(2):141-144, Neuroscience letters
Two (P117L; M146L) familial Alzheimer's disease (FAD)-causing presenilin-1 (PS1) mutations have been tested fortheir effect in stably transfected mouse neuroblastoma (N2a) cell lines. The P117L mutation is associated with the earliest onset of AD reported so far (24 years), while the M146L is less pathogenic with the onset at about 43 years. Overexpression of wild-type (wt) PS1 gene was associated with the marked increase in the number and the length of neuritic outgrowths accompanied by accumulation of PS1 immunoreactivity in neurites. The highly pathogenic P117L mutation completely suppressed this effect and the pattern of PS1 immunolabeling resembled a cup structure with all immunoreactivity gathered at one pole of the cell. The effect of less pathogenic M146L mutation was similar, but not as pronounced. These findings suggest that one of the normal functions of PS1 may be the control of neurite outgrowth, and the inhibitory effect of two FAD-linked mutations stresses its importance in the cellular mechanism that leads to the development of Alzheimer's disease (AD)
— id: 34318, year: 1999, vol: 267, page: 141, stat: Journal Article,

Expression of PS1 mutations linked to familial Alzheimer's disease inhibits neuritic outgrowth
Dowjat, WK; Wisniewski, T; Efthimiopoulos, S; Wisniewski, HM
1999 MAY ;58(5):558-558, Journal of neuropathology & experimental neurology
— id: 54055, year: 1999, vol: 58, page: 558, stat: Journal Article,

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,

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,

ApoE-epsilon 4 allele: Relationship to plasma amyloid beta and ApoE levels in normal elderly
Pomara, N; Shao, B; Wisniewski, T; Mehta, PD
1999 APR 15 ;45(8):274-49, Biological psychiatry
— id: 98321, year: 1999, vol: 45, page: 274, 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,

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,

Light and electron microscopic immunolocalization of presenilin 1 in abnormal muscle fibers of patients with sporadic inclusion-body myositis and autosomal-recessive inclusion-body myopathy
Askanas V; Engel WK; Yang CC; Alvarez RB; Lee VM; Wisniewski T
1998 Apr;152(4):889-895, American journal of pathology
Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older persons. The muscle biopsy demonstrates mononuclear cell inflammation and vacuolated muscle fibers containing paired helical filaments and 6- to 10-nm fibrils, both resembling those of Alzheimer disease brain and Congo red positivity. The term hereditary inclusion-body myopathies (h-IBMs) designates autosomal-recessive or autosomal-dominant disorders with muscle biopsies cytopathologically similar to s-IBM but without inflammation. Vacuolated muscle fibers of both s-IBM and the h-IBMs contain accumulations of several 'Alzheimer-characteristic proteins' including beta-amyloid protein and beta-amyloid precursor protein, and their paired helical filaments are composed of phosphorylated tau. We used six well characterized antibodies against several residues of presenilin 1 (PS1) to immunostain muscle biopsies of 12 patients with s-IBM, 5 patients with autosomal-recessive inclusion-body myopathy, and 16 normal and disease controls. Seventy to eighty percent of the vacuolated muscle fibers of both s-IBM and autosomal-recessive inclusion-body myopathy had inclusions that were strongly PS1-immunoreactive, which by immunoelectron microscopy localized mainly to paired helical filaments and 6- to 10-nm filaments. None of the control biopsies had PS1-positive inclusions characteristic of the s- and h-IBM abnormal muscle fibers. Mutations of the newly discovered PS1 gene are responsible for early-onset familial Alzheimer disease (AD), and PS1 is abnormally accumulated in sporadic and familial AD brain. Our study provides the first demonstration of PS1 abnormality in non-neural tissue and in diseases other than AD and suggests that the cytopathogenesis in AD brain and IBM muscle may share similarities
— id: 7491, year: 1998, vol: 152, page: 889, stat: Journal Article,

Enrichment of presenilin 1 peptides in neuronal large dense-core and somatodendritic clathrin-coated vesicles
Efthimiopoulos, S; Floor, E; Georgakopoulos, A; Shioi, J; Cui, W; Yasothornsrikul, S; Hook, VYH; Wisniewski, T; Buee, L; Robakis, NK
1998 DEC ;71(6):2365-2372, Journal of neurochemistry
Presenilin 1 is an integral membrane protein specifically cleaved to yield an N-terminal and a C-terminal fragment, both membrane-associated. More than 40 presenilin 1 mutations have been linked to early-onset familial Alzheimer disease, although the mechanism by which these mutations induce the Alzheimer disease neuropathology is not clear. Presenilin 1 is expressed predominantly in neurons, suggesting that the familial Alzheimer disease mutants may compromise or change the neuronal function(s) of the wild-type protein. To elucidate the function of this protein, we studied its expression in neuronal vesicular systems using as models the chromaffin granules of the neuroendocrine chromaffin cells and the major categories of brain neuronal vesicles, including the small clear-core synaptic vesicles, the large dense-core vesicles, and the somatodendritic and nerve terminal clathrin-coated vesicles. Both the N- and C-terminal presenilin 1 proteolytic fragments were greatly enriched in chromaffin granule and neuronal large dense-core vesicle membranes, indicating that these fragments are targeted to these vesicles and may regulate the large dense-core vesicle-mediated secretion of neuropeptides and neurotransmitters at synaptic sites, The presenilin 1 fragments were also enriched in the somatodendritic clathrin-coated vesicle membranes, suggesting that they are targeted to the somatodendritic membrane, where they may regulate constitutive secretion and endocytosis. In contrast, these fragments were not enriched in the small clear-core synaptic vesicle or in the nerve terminal clathrin-coated vesicle membranes. Taken together, our data indicate that presenilin 1 proteolytic fragments are targeted to specific populations of neuronal vesicles where they may regulate vesicular function. Although full-length presenilin 1 was present in crude homogenates, it was not detected in any of the vesicles studied, indicating that, unlike the presenilin fragments, full-length protein may not have a vesicular function
— id: 53657, year: 1998, vol: 71, page: 2365, 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,

Decreases in plasma A beta 1-40 levels with aging in non-demented elderly with ApoE-epsilon 4 allele
Pomara N; Shao B; Wisniewski T; Mehta PD
1998 Dec;23(12):1563-1566, Neurochemical research
This report examines plasma amyloid beta proteins A beta 40 and A beta 42 and apolipoprotein E (apoE) levels and their relationships with age in non-demented older adults with (N = 32) or without the apoE-epsilon 4 allele (N = 94). A beta levels did not differ between the groups whereas the epsilon 4 allele was associated with a significant reduction in plasma apoE. In subjects with the epsilon 4 allele, increasing age was associated with significant reduction in plasma A beta 40. Subjects without the epsilon 4 allele showed a significant positive correlation between A beta 40 and A beta 42 levels. There was also a significant correlation between plasma A beta 40 and apoE levels in all subjects
— id: 7747, year: 1998, vol: 23, page: 1563, stat: Journal Article,

Cell-type-specific enhancement of amyloid-beta deposition in a novel presenilin-1 mutation (P117L)
Wegiel J; Wisniewski HM; Kuchna I; Tarnawski M; Badmajew E; Popovitch E; Kulczycki J; Dowjat WK; Wisniewski T
1998 Sep;57(9):831-838, Journal of neuropathology & experimental neurology
The presenilin-1 (PS1) gene mutation (Pro117Leu), recently identified in a Polish family is characterized by the earliest reported onset (from 24-31 years) of Alzheimer disease (AD) and a very short duration of disease (4-6 years). The neuropathology of 2 subjects with this PS1 mutation (ages at death: 35 and 37 years) was compared to four Down syndrome (DS) patients (mean age at death: 62 years) and 4 sporadic AD patients (mean age at death: 79 years with a mean duration of disease of 18 years). The Polish familial AD (FAD) patients showed a marked increase in the amyloid burden of 2 6-fold in most areas of the brain. The entorhinal cortex was an exception where the amyloid burden was similar in each category of patient. Some brain regions of the Polish FAD patients showed a massive increase of amyloid, such as the molecular layer of the cerebellum where a 7- and 25-fold increase was noted, compared with DS and sporadic AD patients respectively. The cerebellar vessel amyloid burden was also greatly increased in the FAD patients, reflecting a vascular compartment specific increase of amyloid beta deposition. The presence of this PS1 mutation has an even greater effect on both vascular and parenchymal amyloid deposition, than the overexpression of the amyloid beta precursor protein present in DS patients, suggesting that PS mutations can be a critical factor determining amyloid deposition
— id: 7843, year: 1998, vol: 57, page: 831, stat: Journal Article,

Brain structure specific enhancement of amyloidosis beta in a novel presenilin-1 mutation (P117L)
Wegiel, J; Wisniewski, HM; Kuchna, I; Tarnawski, M; Badmajew, E; Kulczycki, J; Dowjat, KW; Wisniewski, T
1998 ;57(5):172-80, Journal of neuropathology & experimental neurology
— id: 97620, year: 1998, vol: 57, page: 172, stat: Journal Article,

Pathogenesis of amyloid-beta plaques : activated microglia the cause of fibrillar amyloid formation and neuropil degeneration
Wisniewski HM; Wegiel J; Wisniewski T
1998 ;1:30-34, Neuroscience news
— id: 97676, year: 1998, vol: 1, page: 30, stat: Journal Article,

Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis
Wisniewski KE; Zhong N; Kaczmarski W; Kaczmarski A; Kida E; Brown WT; Schwarz KO; Lazzarini AM; Rubin AJ; Stenroos ES; Johnson WG; Wisniewski TM
1998 Jan;43(1):106-110, Annals of neurology
We present a clinicopathological study and the first molecular genetic analysis of a family with 2 siblings affected by a rare, protracted form of juvenile neuronal ceroid lipofuscinosis (JNCL). Molecular genetic studies showed that both siblings, in addition to being heterozygous for the 1.02-kb CLN3 deletion, a common mutation in JNCL, also had a G-to-A missense mutation at nucleotide 1,020 of the CLN3 cDNA sequence on the non-1.02-kb deletion chromosomes. This point mutation resulted in a substitution of glutamic acid by lysine at position 295 of the CLN3 protein. Thus, a single point mutation at residue 295 of the CLN3 protein in protracted JNCL may underlie the phenotype in this form, which differs from that in classic JNCL
— id: 7858, year: 1998, vol: 43, page: 106, 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,

Alpha B-crystallin is associated with intermediate filaments in astrocytoma cells
Wisniewski T; Goldman JE
1998 Mar;23(3):385-392, Neurochemical research
Alpha B-crystallin, a major protein of the vertebrate lens and a member of the small heat shock protein family, is expressed in non-lenticular tissues, including the central nervous system, where it is found mainly in glia. In Rosenthal fibers (RF), astrocytic inclusions that accumulate in Alexander's Disease, alpha B-crystallin is found with hsp27 and skeins of intermediate filaments (IF) of the GFAP and vimentin types. We have investigated the association between IF and alpha B-crystallin in a human astrocytoma cell line, U-373MG, which expresses alpha B-crystallin. Cytoskeletal preparations contained alpha B-crystallin, and a filamentous pattern in which alpha B-crystallin co-localized with GFAP and vimentin by double label immunofluorescence. Immuno-electronmicroscopy confirmed the localization to IF. GFAP isolated from bovine brain and re-assembled, was associated with alpha B-crystallin. Thus, a proportion of alpha B-crystallin in astroglia is associated with IF, and this association may be critical in the formation of RF
— id: 7857, year: 1998, vol: 23, page: 385, 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,

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,

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,

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,

Micropreparative gel electrophoresis of low-molecular-weight peptides: purification of highly insoluble amyloid peptide fragments
Baumann M; Golabek A; Lalowski M; Wisniewski T
1996 May 1;236(2):191-198, Analytical biochemistry
We have used the continuous-elution micropreparative gel electrophoresis device described by Baumann and Lauraeus (Anal. Biochem. 214, 142-148, 1993) to purify low-molecular-weight peptide fragments from in-gel digested standard proteins as well as highly in-soluble amyloid peptides. Alzheimer's amyloid beta-peptide, gelsolin-derived amyloid peptide of the Finnish type, and a novel amyloid of the British type were purified from either homogenized brain or kidney tissue material to a high degree of purity in a single run. Using the high resolving capacity of the Tris-Tricine-SDS buffer system of Schaegger and von Jagow (Anal. Biochem. 166, 368-379, 1978) we were able to isolate two synthetic peptides with M(r)4329 and 3284, differing only by 1045 in mass. The total peptide recovery, as determined by amino acid sequence analysis and scanning densitometry, ranged between 60 and 80%. In order to demonstrate the utility of this technique we subjected some of the purified peptides to direct N-terminal amino acid sequence analysis, mass spectrometry, microbore high-performance liquid chromatography, and immunochemical studies. Our results show that micropreparative gel electrophoresis is an effective tool for the isolation of not only larger polypeptides but also small peptide fragments in a form suitable for further biological use
— id: 12618, year: 1996, vol: 236, page: 191, stat: Journal Article,

C-terminal fragments of alpha- and beta-tubulin form amyloid fibrils in vitro and associate with amyloid deposits of familial cerebral amyloid angiopathy, British type
Baumann MH; Wisniewski T; Levy E; Plant GT; Ghiso J
1996 Feb 6;219(1):238-242, Biochemical & biophysical research communications
Familial amyloidosis, British type, is an autosomal dominant disease characterized by progressive dementia, spastic paralysis and ataxia. The identity of the accumulating amyloid is not known, thus preventing the definitive classification of the disease. Biochemical methods were used to characterize the nature of the amyloid deposits from the brain tissue of one individual who died with this disease. The purified tissue material was subjected to trypsin digestion and subsequent N-terminal sequence analysis. Major tryptic fragments yielded the sequences VGINYQPPTVVPGGDLAK, FDLMYAK, GLTVPEL and GYLTVAAVFR, which are all tryptic fragments of the C-termini of human tubulin subunits alpha and beta. Synthetic peptides based on the sequences of these fragments formed amyloid fibrils in vitro fitting the characteristic definition of amyloid. These findings suggest that the C-terminal fragments of both alpha- and beta-tubulin are closely associated to the amyloid deposits of familial amyloidosis, British type
— id: 6886, year: 1996, vol: 219, page: 238, stat: Journal Article,

Medical conditions in Alzheimer's disease patients with 4/4 isotype of apolipoprotein E
Boksay, I.; Tchernkov, K.; Myint, Z.; Reisberg, B.; Wisniewski, T.
1996 ;17(4 SUPPL.):S125-S126, Neurobiology of aging
— id: 97598, year: 1996, vol: 17, page: S125, 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,

Familial meningocerebrovascular amyloidosis, Hungarian type, with mutant transthyretin (TTR Asp18Gly)
Garzuly, F; Wisniewski, T; Brittig, F; Budka, H
1996 DEC ;47(6):1562-1567, Neurology
Amyloid deposits in leptomeningeal vessels, subarachnoid, subpial, and subependymal cerebrospinal regions, spinal ganglia, peripheral nerves, and some internal organs (predominantly heart and kidney) characterize a dominantly inherited disease in a Hungarian family. We found four definitely and three probably affected members in this family of 56 persons in four generations. Clinical features in all definitely diseased patients include disturbance of memory, psychomotor deceleration, ataxia, and hearing loss. In most patients there was temporary disorientation, migraine-like headache with vomiting, and tremor. Some patients had nystagmus, pyramidal signs with spastic paraparesis, hallucinations, urinary retention, and obstipation. Single patients had facial ties and sleep disorders. Progressive visual disturbance and clinically manifest polyneuropathy were absent. CSF protein was markedly elevated in all patients. CT showed characteristic symmetric calcification along the sylvian fissure; MRI after contrast administration showed prominent enhancement at the surface of the sylvian fissures, brainstem, and cerebellum. Autopsy data was available in three definitely affected patients and in one unaffected family member. Immunohistochemistry identified the amyloid deposits as of the AF (transthyretin, TTR) type; DNA studies revealed a novel TTR missense mutation at codon 18 (TTR Asp18Gly). According to clinical features, pathologic alterations, and molecular studies, this disease is a novel type of systemic familial amyloidosis with disease manifestation clinically restricted to the CNS. It is similar to the oculoleptomeningeal amyloidoses but can be clinically diagnosed by characteristic CTs and the absence of progressive visual impairment
— id: 52687, year: 1996, vol: 47, page: 1562, stat: Journal Article,

The interaction between apolipoprotein E and Alzheimer's amyloid beta-peptide is dependent on beta-peptide conformation
Golabek AA; Soto C; Vogel T; Wisniewski T
1996 May 3;271(18):10602-10606, Journal of biological chemistry
An important feature of Alzheimer's disease (AD) is the cerebral deposition of amyloid. The main component of the amyloid is a 39-44-amino acid residue protein called amyloid beta (A beta), which also exists as a normal protein in biological fluids, known as soluble A beta. A major risk factor for late-onset AD is the inheritance of the apolipoprotein (apo) E4 isotype of apoE. How apoE is involved in the pathogenesis of AD is unclear; however, evidence exists for a direct apoE/A beta interaction. We and others have shown that apoE copurifies with A beta from AD amyloid plaques and that under certain in vitro conditions apoE promotes a beta-sheet structure in A beta peptides. Currently we document the high affinity binding of A beta peptides to both human recombinant apoE3 and -E4 with a KD of 20 nM. This interaction is greatly influenced by the conformational state of the A beta peptide used. Furthermore, we show that the fibril modulating effect of apoE is also influenced by the initial secondary structure of the A beta peptide. The preferential binding of apoE to A beta peptides with a beta-sheet conformation can in part explain the copurification of A beta and apoE from AD amyloid plaques
— id: 6997, year: 1996, vol: 271, page: 10602, stat: Journal Article,

Binding between apolipoprotein E and amyloid beta is dependent on secondary structure
Golabek, A. A.; Soto, C.; Wisniewski, T.
1996 ;17(4 SUPPL.):S174-S126, Neurobiology of aging
— id: 97599, year: 1996, vol: 17, page: S174, stat: Journal Article,

The interaction between apolipoprotein E and Alzheimer's amyloid beta-peptide is dependent on beta-peptide conformation
Golabek, AA; Soto, C; Wisniewski, T
1996 MAY ;55(5):150-150, Journal of neuropathology & experimental neurology
— id: 52926, year: 1996, vol: 55, page: 150, 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,

Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation
Lemere CA; Blusztajn JK; Yamaguchi H; Wisniewski T; Saido TC; Selkoe DJ
1996 Feb;3(1):16-32, Neurobiology of disease
Patients with trisomy 21 [Down syndrome (DS)] progressively develop amyloid beta-protein (A beta) deposits and then other features of Alzheimer's disease (AD), apparently due to increased gene dosage and thus expression of the beta-amyloid precursor protein. Because the neuropathological phenotype in older DS subjects closely resembles that of AD, the examination of DS brains of increasing age provides a unique model of the progression of AD. Here, we characterized the deposition of several A beta peptides and apolipoprotein E in formalin-fixed brain sections from 29 DS subjects between 3 and 73 years old. Amyloid plaque number and the percentage of cortical area they occupied were quantified by computerized image analysis. A beta ending at amino acid 42 (A beta 42) was the earliest form of A beta deposited in DS cortex. It was observed in 7 of 16 young (3-30 years) subjects, with the earliest deposition occurring at age 12. A beta ending at residue 40 (A beta 40) was not detected until approximately age 30, a time when degenerating neurites around A beta immunoreactive (IR) plaques were first observed, and the frequency of A beta 40 IR plaques then rose with age. Even in old (51-73 years) DS subjects, A beta 42 IR plaques were always more abundant than A beta 40 IR plaques. A beta peptides starting at aspartate 1 or pyroglutamate 3 were detected in small subsets of compacted, neuritic plaques beginning around age 30 and rose with age, the latter species always exceeding the former. Thus, the N-termini of the A beta 42 peptides abundantly deposited in very young DS subjects remain unknown. Apo E was detectable in a small subset of A beta 42 IR plaques beginning at age 12 and rose steadily with age; it clearly followed the deposition of A beta. Our analysis of very young DS brains suggests that amyloid plaque formation begins with A beta 42-ending peptides, and the number and percentage of cortical area of A beta 42 plaques increase very little with advancing age, while other heterogeneous A beta species and Apo E progressively accrue onto plaques containing A beta 42
— id: 34319, year: 1996, vol: 3, page: 16, 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,

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,

Alzheimer's beta-amyloid peptide is conformationally modified by apolipoprotein E in vitro
Soto C; Golabek A; Wisniewski T; Castano EM
1996 Feb 29;7(3):721-725, Neuroreport
Amyloid beta-peptide (A beta) is a major component of neuritic plaques, a feature of Alzheimer's disease (AD) brains. Recently, we showed that A beta adopts two major conformational states in solution, which differ in their abilities to form amyloid. These are highly amyloidogenic conformer (A beta ac) with a high content of beta-sheet and a slowly amyloidogenic conformer (A beta nac) with a random coil conformation. Apolipoprotein E (apoE), particularly the E4 isoform, which is genetically associated with AD, binds to A beta and modulates fibrillogenesis in vitro. In the present work, the influence of apoE on the conformation of A beta peptides was studied. The results suggest that, under the conditions used, apoE enhances amyloid formation by inducing the conformational transition from A beta nac into A beta ac. We propose that an important step in A beta fibrillogenesis is the transformation induced by apoE of the soluble non-amyloidogenic into the pathological amyloidogenic conformer of A beta
— id: 7091, year: 1996, vol: 7, page: 721, 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,

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,

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,

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,

Amyloid beta binding proteins in vitro and in normal human cerebrospinal fluid
Golabek A; Marques MA; Lalowski M; Wisniewski T
1995 May 19;191(1-2):79-82, Neuroscience letters
A major neuropathological feature of Alzheimer's disease (AD) is the deposition of amyloid beta (A beta) in the form of senile plaques. The A beta peptide exists both in a beta-pleated sheet fibrillar form in amyloid deposits and as a normal soluble protein in biological fluids. Numerous proteins have been identified immunohistochemically to be associated with senile plaques, where A beta is the major constituent. Some of the latter have also been suggested to be carriers of the normal soluble A beta (sA beta) including apolipoprotein J (apoJ), apolipoprotein E (apoE) and transthyretin (TTR). We have found, using several different methods, that numerous proteins can bind synthetic A beta peptides when high concentrations are used; however, using an affinity anti-sA beta column we confirm that apoJ is the major binding protein in pooled human cerebrospinal fluid. On the other hand it is known that apoE co-purifies with A beta biochemically extracted from senile plaques. In AD tissue there may be a change in the major apolipoprotein binding A beta from apoJ to apoE
— id: 6629, year: 1995, vol: 191, page: 79, 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,

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,

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,

Neurology for non-neurologists
Weinreb, Herman J.; Chou, James C.-Y.; Wisniewski, Thomas; Golomb, Jamie; Hiesiger, Emile M.; Sussman, Norman; Rapoport, David; Henry, Katherine; Krishna, Ranga; Kricheff, Irvin I.; Stiller, Keith
[Irvington, NY] : Pass the Boards, c1995,
— id: 512, year: 1995, vol: , page: , stat: ,

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,

The origin of A-beta in plaques and vessels in aging and Alzheimer disease
Wisniewski, H. M.; Wegiel, J.; Frackowiak, J.; Wisniewski, T.
1995 ;55(SUPPL.):42-221, Acta neurobiologiae experimentalis
— id: 97628, year: 1995, vol: 55, page: 42, 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,

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,

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,

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,

Regional differences in apolipoprotein E immunoreactivity in diffuse plaques in Alzheimer's disease brain
Kida, E; Golabek, A A; Wisniewski, T; Wisniewski, K E
1994 Feb 14;167(1-2):73-76, Neuroscience letters
Apolipoprotein E (Apo E) has been shown to be closely associated with beta amyloid in Alzheimer's disease (AD) brain. In the present study, we have found strong Apo E immunoreactivity in the amyloid cores of senile plaques (SP) in the various brain regions examined. However, Apo E immunoreactivity in diffuse plaques varied distinctly and was strong within numerous cerebellar and cortical diffuse plaques, and absent or very weak within diffuse plaques in the striatum/thalamus. This distribution of Apo E immunoreactivity in SP correlates with the occurrence of small amounts of fibrillar amyloid in diffuse plaques that has been described in the cerebral and cerebellar cortex, but not in the basal ganglia. These results show that Apo E may be associated with sites of beta amyloid fibril formation in diffuse plaques in AD brain, but they also suggest that factors other than Apo E, probably local, may influence fibrillogenesis
— id: 97586, year: 1994, vol: 167, page: 73, 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,

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,

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,

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,

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,

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,

The adult and a new late adult forms of neuronal ceroid lipofuscinosis
Constantinidis J; Wisniewski KE; Wisniewski TM
1992 ;83(5):461-468, Acta neuropathologica
Three cases of the late adult form of neuronal ceroid lipofuscinosis (NCL) are reported. Two of these are siblings with a late clinical onset at ages 26 and 44 years. The third case, sporadic, has the oldest reported age for the onset of NCL, at 63 years and may be regarded as the first example of the 'presenile' form of NCL. The clinical, morphological, histochemical, ultrastructural and genetic features of these three cases are discussed. The literature of the clinicopathological NCL cases with an onset at age of 25 and older is reviewed. The clinical and morphological differences between the late adult form and the presenile form of NCL as well as the difficulties in making the diagnosis are discussed
— id: 23491, year: 1992, vol: 83, page: 461, 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,

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,

Accumulation of alpha B-crystallin in central nervous system glia and neurons in pathologic conditions
Iwaki, T; Wisniewski, T; Iwaki, A; Corbin, E; Tomokane, N; Tateishi, J; Goldman, J E
1992 Feb;140(2):345-356, American journal of pathology
Alpha B-crystallin, a major protein of the vertebrate lens, is found in the central nervous system (CNS) and is a major protein component of Rosenthal fibers (RF), intracytoplasmic inclusions within astrocytes. Its level of expression in the normal CNS is low and appears to be confined to glial cells, both astrocytes and oligodendrocytes. A number of human brains displaying a variety of pathologic changes were examined by immunohistochemistry with an anti-alpha B-crystallin antiserum and increased immunoreactivity was found in astrocytes and oligodendrocytes without the formation of RFs. Furthermore, some neurons in neurodegenerative disorders were also immunolabeled with the anti-alpha B-crystallin antiserum. Thus, the accumulation of alpha B-crystallin appears to be part of the repertoire of reactive processes of CNS glial cells and some neurons in pathologic conditions
— id: 97585, year: 1992, vol: 140, page: 345, stat: Journal Article,

Pituitary apoplexy
Post K; Onesti S; Wisniewski T
Intracerebral hematomas New York : Raven Press, 1992,
— id: 4973, year: 1992, vol: , page: ?, stat: Chapter,

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,

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,

Alzheimer's disease and the cerebral amyloidoses
Wisniewski TM; Wisniewski HM
Neurodevelopment, aging, and cognition Boston : Birkhauser, 1992,
— id: 4981, year: 1992, vol: , page: 157, stat: Chapter,

Alzheimer's disease and the cerebral amyloidoses
Wisniewski, Thomas M; Wisniewski, Henryk M
Neurodevelopment, aging and cognition Cambridge, MA, US: Birkhauser; US, 1992,
Discusses the accumulation of amyloid in the cerebrum of Alzheimer's disease patients. (from the chapter) amyloid and the systemic amyloidoses / cerebral amyloidoses / biochemical and molecular studies of Alzheimer's disease
— id: 5416, year: 1992, vol: , page: 157, stat: Chapter,

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,

The dominant form of the pigmentary orthochromatic leukodystrophy
Constantinidis J; Wisniewski TM
1991 ;82(6):483-487, Acta neuropathologica
The present report documents a family with three cases in two successive generations of pigmentary orthochromatic leukodystrophy (POLD). The clinical features of these cases and histochemical and ultrastructural investigations of two of the brains from successive generations are discussed. A review of the familial cases of POLD reported in the literature is also presented. Transmission of these cases was by a dominant inheritance. Onset of the clinical symptoms occurred at 42 to 54 years of age; duration of the disease was from 2-11 years, and death occurred at 45 to 57 years of age. Clinical manifestations of all three cases were severe headaches; bilateral pyramidal, pseudobulbar, cerebellar, and frontal release signs; gait disturbances; euphoria, or apathy; epileptic seizures; and dementia. The neuropathological pattern consists of slight cerebral atrophy, brownish discoloration of the cerebral white matter with demyelination and severe gliosis, sparing the sub-cortical U fibers; presence in the macrophages of lipid pigment granules that are sudanophilic, non metachromatic, and PAS and iron positive. The electron microscopic pattern of the lipid pigment in the macrophages is that of ceroid: electron-dense, membrane-bound intracytoplasmic lysosomes with curvilinear and/or fingerprint profiles
— id: 23492, year: 1991, vol: 82, page: 483, 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,

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,

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,

Beta-protein immunoreactivity in brains of patients with neuronal ceroid lipofuscinosis: ultrastructural and biochemical demonstration
Kitaguchi T; Wisniewski KE; Maslinski S; Maslinska D; Wisniewski TM; Kim KS
1990 May 4;112(2-3):155-160, Neuroscience letters
The storage pigment in neuronal ceroid lipofuscinoses (NCL) has a close similarity to age pigment lipofuscin. We studied immunoreactivity of isolated neuronal pigments from the juvenile form of NCL and aging control, using monoclonal antibodies (mAbs) against amyloid beta-protein. Ultrastructural localization of the immunoreactivity demonstrated that in NCL the epitopes are distributed mainly in curvilinear multilamellar arrays of the storage pigments and less in fingerprint profiles, while in aging control they are more homogeneously distributed on age pigment lipofuscin. The different distribution of the epitopes may reflect some catabolic as well as morphologic differences in lysosomes. A unique 31-kDa polypeptide detected on Western blots in NCL possibly derives from the same precursor, amyloid beta-protein precursor (ABPP). ABPP processing may be aberrant in NCL brains, and this can be detected as a 31-kDa polypeptide reactive with the mAbs
— id: 23493, year: 1990, vol: 112, page: 155, stat: Journal Article,

Clinical versus subclinical pituitary apoplexy: presentation, surgical management, and outcome in 21 patients
Onesti, S T; Wisniewski, T; Post, K D
1990 Jun;26(6):980-986, Neurosurgery
A retrospective review of 16 consecutive patients with pituitary apoplexy treated over a 10-year period is reported. Eight men and 8 women (mean age, 48 years) underwent transsphenoidal decompression after an average duration of symptoms of 19 days. The diagnosis of pituitary apoplexy was made by the sudden onset of headache (88%), nausea (56%), or meningismus (13%), with or without visual disturbances (75%), in the setting of a sellar tumor on computed tomographic or magnetic resonance imaging scans. Thirteen of 16 patients showed significant improvement of symptoms after surgery (average follow-up, 2.5 years). In addition, 5 patients with clinically silent yet extensive pituitary hemorrhage were treated. Although extensive pituitary hemorrhage often produced fulminant apoplexy, it also presented insidiously over many days with few, if any, clinical signs. Rapid diagnosis, endocrine replacement, and transsphenoidal decompression constituted effective therapy. Magnetic resonance imaging (after at least 12 hours of symptoms) was superior to computed tomography in detecting hemorrhage
— id: 97582, year: 1990, vol: 26, page: 980, stat: Journal Article,

Pituitary hemorrhage into a Rathke's cleft cyst
Onesti, S T; Wisniewski, T; Post, K D
1990 Oct;27(4):644-646, Neurosurgery
This report describes a case of symptomatic pituitary hemorrhage into a Rathke's cleft cyst in a 25-year-old woman. The literature on pituitary hemorrhage in nonadenomatous sellar tumors is reviewed
— id: 97583, year: 1990, vol: 27, page: 644, stat: Journal Article,

Intracerebral solitary plasmacytoma
Wisniewski, T; Sisti, M; Inhirami, G; Knowles, D M; Powers, J M
1990 Nov;27(5):826-829, Neurosurgery
We report a rare occurrence of intraparenchymal plasmacytoma and review the literature. The clonal nature of the neoplasm is demonstrated by immunohistochemical and molecular techniques. The importance of the latter techniques in ruling out other pathological entities is stressed
— id: 97584, year: 1990, vol: 27, page: 826, stat: Journal Article,

Partial purification of neurofilament subunits from bovine brains and studies on neurofilament assembly
Moon, H M; Wisniewski, T; Merz, P; De Martini, J; Wisniewski, H M
1981 Jun;89(3):560-567, Journal of cell biology
The 200,000-dalton neurofilament subunit (P200) and the 160,000-dalton (P160) and 78,000-dalton (P78) neurofilament subunits were partially purified from bovine brain. Intact neurofilaments were prepared by high-speed and sucrose-zone centrifugation. The crude neurofilament was solubilized in 8 M urea solution containing pyridine, formic acid, and 2-mercaptoethanol. The solubilized neurofilament was purified by carboxymethyl (CM) cellulose column and hydroxylapatite column chromatography. The P200 was purified as separate from P160 and P78, but the P160 and P78 subunits were copurified on CM cellulose, hydroxylapatite, Bio-Gel A150m, and Sephadex G-150 column chromatography. Electron microscopy of these purified neurofilament subunits revealed the P200 subunit as a globular structure, and the P160 and P78 subunits as a rod-shaped structure extending up to 120 nm with a 8- to 12-nm width. In the presence of 200 mM KCl, 15 mM MgCl2, and 1 mM ATP, the purified subunits assembled into long filaments. Under the assembly condition, P160 and P78 subunits elongated up to 500 nm, but the longer filament formation required the presence of P200 subunits. The filaments formed in vitro were of two types: long straight filaments and intertwined knobby-type filaments. From these results, we have suggested that P160 and P78 form the neurofilament backbone structure and P200 facilitates the assembly of the backbone units into longer filaments
— id: 97581, year: 1981, vol: 89, page: 560, stat: Journal Article,