Paul M. Mathews, Ph.D.

Alzheimer-specific variants in the 3'UTR of Amyloid precursor protein affect microRNA function
Delay, Charlotte; Calon, Frederic; Mathews, Paul; Hebert, Sebastien S
2011 ;6:70-70, Molecular neurodegeneration
ABSTRACT: BACKGROUND: APP expression misregulation can cause genetic Alzheimer's disease (AD). Recent evidences support the hypothesis that polymorphisms located in microRNA (miRNA) target sites could influence the risk of developing neurodegenerative disorders such as Parkinson's disease (PD) and frontotemporal dementia. Recently, a number of single nucleotide polymorphisms (SNPs) located in the 3'UTR of APP have been found in AD patients with family history of dementia. Because miRNAs have previously been implicated in APP expression regulation, we set out to determine whether these polymorphisms could affect miRNA function and therefore APP levels. RESULTS: Bioinformatics analysis identified twelve putative miRNA bindings sites located in or near the APP 3'UTR variants T117C, A454G and A833C. Among those candidates, seven miRNAs, including miR-20a, miR-17, miR-147, miR-655, miR-323-3p, miR-644, and miR-153 could regulate APP expression in vitro and under physiological conditions in cells. Using luciferase-based assays, we could show that the T117C variant inhibited miR-147 binding, whereas the A454G variant increased miR-20a binding, consequently having opposite effects on APP expression. CONCLUSIONS: Taken together, our results provide proof-of-principle that APP 3'UTR polymorphisms could affect AD risk through modulation of APP expression regulation, and set the stage for further association studies in genetic and sporadic AD
— id: 140551, year: 2011, vol: 6, page: 70, stat: Journal Article,

Catabolism of Alzheimer's amyloid-b: Implications for brain clearance and plaque deposition
McIntee F.L.; Giannoni P.; Blais S.; Neubert T.; Mathews P.; Rostagno A.; Ghiso J.
2011 ;8:?-?, Neuro-degenerative diseases
Alzheimer's disease (AD) is the leading cause of dementia and the most common form of amyloidosis in humans. Extensive extracellular deposition of amyloid-beta (Abeta), a 40-42 amino acid degradation product of APP, is considered a hallmark feature of AD. Our attention is focused on the highly heterogeneous biochemical nature of the brain Abeta species, delving beyond Abeta40 and Abeta42, likely reflecting a complex balance between amyloidogenic and clearance pathways. We have fractionated water-soluble, detergent-soluble and formic acid soluble Abeta species from brains of transgenic mouse models of amyloid depostion and AD cases. Subsequently, we applied a combination of biochemical techniques including immunoprecipitation followed by identification of Abeta species with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Our biochemical data on the Abeta species present in sporadic AD cases and in transgenic mouse models highlight the presence of similar N-and C-terminally truncated fragments-likely reflecting the ability of multiple proteases to degrade Abeta in situ-and several post-translational modifications with still unclear roles in the amyloidogenesis mechanism. Notably, not all the brain Abeta peptides have identical solubility properties; whereas many of them are highly soluble in water-based physiologic solutions others require mild detergents or strong acids for extraction, suggesting their differential involvement in catabolic and fibrillogenic processes
— id: 136531, year: 2011, vol: 8, page: ?, stat: Journal Article,

Synaptic Autoregulation by Metalloproteases and {gamma}-Secretase
Restituito, Sophie; Khatri, Latika; Ninan, Ipe; Mathews, Paul M; Liu, Xin; Weinberg, Richard J; Ziff, Edward B
2011 Aug 24;31(34):12083-12093, Journal of neuroscience
The proteolytic machinery comprising metalloproteases and gamma-secretase, an intramembrane aspartyl protease involved in Alzheimer's disease, cleaves several substrates in addition to the extensively studied amyloid precursor protein. Some of these substrates, such as N-cadherin, are synaptic proteins involved in synapse remodeling and maintenance. Here we show, in rats and mice, that metalloproteases and gamma-secretase are physiologic regulators of synapses. Both proteases are synaptic, with gamma-secretase tethered at the synapse by delta-catenin, a synaptic scaffolding protein that also binds to N-cadherin and, through scaffolds, to AMPA receptor and a metalloprotease. Activity-dependent proteolysis by metalloproteases and gamma-secretase takes place at both sides of the synapse, with the metalloprotease cleavage being NMDA receptor-dependent. This proteolysis decreases levels of synaptic proteins and diminishes synaptic transmission. Our results suggest that activity-dependent substrate cleavage by synaptic metalloproteases and gamma-secretase modifies synaptic transmission, providing a novel form of synaptic autoregulation
— id: 136951, year: 2011, vol: 31, page: 12083, stat: Journal Article,

Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis
Yang, Dun-Sheng; Stavrides, Philip; Mohan, Panaiyur S; Kaushik, Susmita; Kumar, Asok; Ohno, Masuo; Schmidt, Stephen D; Wesson, Daniel W; Bandyopadhyay, Urmi; Jiang, Ying; Pawlik, Monika; Peterhoff, Corrinne M; Yang, Austin J; Wilson, Donald A; St George-Hyslop, Peter; Westaway, David; Mathews, Paul M; Levy, Efrat; Cuervo, Ana M; Nixon, Ralph A
2011 Jul 1;7(7):788-789, Autophagy
The extensive autophagic-lysosomal pathology in Alzheimer disease (AD) brain has revealed a major defect: in the proteolytic clearance of autophagy substrates. Autophagy failure contributes on several levels to AD pathogenesis and has become an important therapeutic target for AD and other neurodegenerative diseases. We recently observed broad therapeutic effects of stimulating autophagic-lysosomal proteolysis in the TgCRND8 mouse model of AD that exhibits defective proteolytic clearance of autophagic substrates, robust intralysosomal amyloid-beta peptide (Abeta) accumulation, extracellular beta-amyloid deposition and cognitive deficits. By genetically deleting the lysosomal cysteine protease inhibitor, cystatin B (CstB), to selectively restore depressed cathepsin activities, we substantially cleared Abeta, ubiquitinated proteins and other autophagic substrates from autolysosomes/lysosomes and rescued autophagic-lysosomal pathology, as well as reduced total Abeta40/42 levels and extracellular amyloid deposition, highlighting the underappreciated importance of the lysosomal system for Abeta clearance. Most importantly, lysosomal remediation prevented the marked learning and memory deficits in TgCRND8 mice. Our findings underscore the pathogenic significance of autophagic-lysosomal dysfunction in AD and demonstrate the value of reversing this dysfunction as an innovative therapeautic strategy for AD
— id: 134440, year: 2011, vol: 7, page: 788, stat: Journal Article,

Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits
Yang, Dun-Sheng; Stavrides, Philip; Mohan, Panaiyur S; Kaushik, Susmita; Kumar, Asok; Ohno, Masuo; Schmidt, Stephen D; Wesson, Daniel; Bandyopadhyay, Urmi; Jiang, Ying; Pawlik, Monika; Peterhoff, Corrinne M; Yang, Austin J; Wilson, Donald A; St George-Hyslop, Peter; Westaway, David; Mathews, Paul M; Levy, Efrat; Cuervo, Ana M; Nixon, Ralph A
2011 Jan;134(Pt 1):258-277, Brain
Autophagy, a major degradative pathway for proteins and organelles, is essential for survival of mature neurons. Extensive autophagic-lysosomal pathology in Alzheimer's disease brain contributes to Alzheimer's disease pathogenesis, although the underlying mechanisms are not well understood. Here, we identified and characterized marked intraneuronal amyloid-beta peptide/amyloid and lysosomal system pathology in the Alzheimer's disease mouse model TgCRND8 similar to that previously described in Alzheimer's disease brains. We further establish that the basis for these pathologies involves defective proteolytic clearance of neuronal autophagic substrates including amyloid-beta peptide. To establish the pathogenic significance of these abnormalities, we enhanced lysosomal cathepsin activities and rates of autophagic protein turnover in TgCRND8 mice by genetically deleting cystatin B, an endogenous inhibitor of lysosomal cysteine proteases. Cystatin B deletion rescued autophagic-lysosomal pathology, reduced abnormal accumulations of amyloid-beta peptide, ubiquitinated proteins and other autophagic substrates within autolysosomes/lysosomes and reduced intraneuronal amyloid-beta peptide. The amelioration of lysosomal function in TgCRND8 markedly decreased extracellular amyloid deposition and total brain amyloid-beta peptide 40 and 42 levels, and prevented the development of deficits of learning and memory in fear conditioning and olfactory habituation tests. Our findings support the pathogenic significance of autophagic-lysosomal dysfunction in Alzheimer's disease and indicate the potential value of restoring normal autophagy as an innovative therapeutic strategy for Alzheimer's disease
— id: 126481, year: 2011, vol: 134, page: 258, stat: Journal Article,

Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease
Coomaraswamy, Janaky; Kilger, Ellen; Wolfing, Heidrun; Schafer, Claudia; Kaeser, Stephan A; Wegenast-Braun, Bettina M; Hefendehl, Jasmin K; Wolburg, Hartwig; Mazzella, Matthew; Ghiso, Jorge; Goedert, Michel; Akiyama, Haruhiko; Garcia-Sierra, Francisco; Wolfer, David P; Mathews, Paul M; Jucker, Mathias
2010 Apr 27;107(17):7969-7974, Proceedings of the National Academy of Sciences of the United States of America
Familial Danish dementia (FDD) is a progressive neurodegenerative disease with cerebral deposition of Dan-amyloid (ADan), neuroinflammation, and neurofibrillary tangles, hallmark characteristics remarkably similar to those in Alzheimer's disease (AD). We have generated transgenic (tg) mouse models of familial Danish dementia that exhibit the age-dependent deposition of ADan throughout the brain with associated amyloid angiopathy, microhemorrhage, neuritic dystrophy, and neuroinflammation. Tg mice are impaired in the Morris water maze and exhibit increased anxiety in the open field. When crossed with TauP301S tg mice, ADan accumulation promotes neurofibrillary lesions, in all aspects similar to the Tau lesions observed in crosses between beta-amyloid (Abeta)-depositing tg mice and TauP301S tg mice. Although these observations argue for shared mechanisms of downstream pathophysiology for the sequence-unrelated ADan and Abeta peptides, the lack of codeposition of the two peptides in crosses between ADan- and Abeta-depositing mice points also to distinguishing properties of the peptides. Our results support the concept of the amyloid hypothesis for AD and related dementias, and suggest that different proteins prone to amyloid formation can drive strikingly similar pathogenic pathways in the brain
— id: 137823, year: 2010, vol: 107, page: 7969, stat: Journal Article,

Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition
Jiang, Ying; Mullaney, Kerry A; Peterhoff, Corrinne M; Che, Shaoli; Schmidt, Stephen D; Boyer-Boiteau, Anne; Ginsberg, Stephen D; Cataldo, Anne M; Mathews, Paul M; Nixon, Ralph A
2010 Jan 26;107(4):1630-1635, Proceedings of the National Academy of Sciences of the United States of America
An additional copy of the beta-amyloid precursor protein (APP) gene causes early-onset Alzheimer's disease (AD) in trisomy 21 (DS). Endosome dysfunction develops very early in DS and AD and has been implicated in the mechanism of neurodegeneration. Here, we show that morphological and functional endocytic abnormalities in fibroblasts from individuals with DS are reversed by lowering the expression of APP or beta-APP-cleaving enzyme 1 (BACE-1) using short hairpin RNA constructs. By contrast, endosomal pathology can be induced in normal disomic (2N) fibroblasts by overexpressing APP or the C-terminal APP fragment generated by BACE-1 (betaCTF), all of which elevate the levels of betaCTFs. Expression of a mutant form of APP that cannot undergo beta-cleavage had no effect on endosomes. Pharmacological inhibition of APP gamma-secretase, which markedly reduced Abeta production but raised betaCTF levels, also induced AD-like endosome dysfunction in 2N fibroblasts and worsened this pathology in DS fibroblasts. These findings strongly implicate APP and the betaCTF of APP, and exclude Abeta and the alphaCTF, as the cause of endocytic pathway dysfunction in DS and AD, underscoring the potential multifaceted value of BACE-1 inhibition in AD therapeutics
— id: 126490, year: 2010, vol: 107, page: 1630, stat: Journal Article,

Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic mice
Bernardo, Alexandra; Harrison, Fiona E; McCord, Meghan; Zhao, Jiali; Bruchey, Aleksandra; Davies, Sean S; Jackson Roberts, L 2nd; Mathews, Paul M; Matsuoka, Yasuji; Ariga, Toshio; Yu, Robert K; Thompson, Rebecca; McDonald, Michael P
2009 Nov;30(11):1777-1791, Neurobiology of aging
Gangliosides have been shown to be necessary for beta-amyloid (Abeta) binding and aggregation. GD3 synthase (GD3S) is responsible for biosynthesis of the b- and c-series gangliosides, including two of the four major brain gangliosides. We examined Abeta-ganglioside interactions in neural tissue from mice lacking the gene coding for GD3S (St8sia1), and in a double-transgenic (APP/PSEN1) mouse model of Alzheimer's disease cross-bred with GD3S-/- mice. In primary neurons and astrocytes lacking GD3S, Abeta-induced cell death and Abeta aggregation were inhibited. Like GD3S-/- and APP/PSEN1 double-transgenic mice, APP/PSEN1/GD3S-/- 'triple-mutant' mice are indistinguishable from wild-type mice on casual examination. APP/PSEN1 double-transgenics exhibit robust impairments on a number of reference-memory tasks. In contrast, APP/PSEN1/GD3S-/- triple-mutant mice performed as well as wild-type control and GD3S-/- mice. Consistent with the behavioral improvements, both aggregated and unaggregated Abeta and associated neuropathology were almost completely eliminated in triple-mutant mice. These results suggest that GD3 synthase may be a novel therapeutic target to combat the cognitive deficits, amyloid plaque formation, and neurodegeneration that afflict Alzheimer's patients
— id: 95388, year: 2009, vol: 30, page: 1777, stat: Journal Article,

Age-dependent dysregulation of brain amyloid precursor protein in the Ts65Dn Down syndrome mouse model
Choi, Jennifer H K; Berger, Jason D; Mazzella, Matthew J; Morales-Corraliza, Jose; Cataldo, Anne M; Nixon, Ralph A; Ginsberg, Stephen D; Levy, Efrat; Mathews, Paul M
2009 Sep;110(6):1818-1827, Journal of neurochemistry
Individuals with Down syndrome develop beta-amyloid deposition characteristic of early-onset Alzheimer's disease (AD) in mid-life, presumably because of an extra copy of the chromosome 21-located amyloid precursor protein (App) gene. App mRNA and APP metabolite levels were assessed in the brains of Ts65Dn mice, a mouse model of Down syndrome, using quantitative PCR, western blot analysis, immunoprecipitation, and ELISAs. In spite of the additional App gene copy, App mRNA, APP holoprotein, and all APP metabolite levels in the brains of 4-month-old trisomic mice were not increased compared with the levels seen in diploid littermate controls. However starting at 10 months of age, brain APP levels were increased proportional to the App gene dosage imbalance reflecting increased App message levels in Ts65Dn mice. Similar to APP levels, soluble amino-terminal fragments of APP (sAPPalpha and sAPPbeta) were increased in Ts65Dn mice compared with diploid mice at 12 months but not at 4 months of age. Brain levels of both Abeta40 and Abeta42 were not increased in Ts65Dn mice compared with diploid mice at all ages examined. Therefore, multiple mechanisms contribute to the regulation towards diploid levels of APP metabolites in the Ts65Dn mouse brain
— id: 126493, year: 2009, vol: 110, page: 1818, stat: Journal Article,

Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia
Grathwohl, Stefan A; Kalin, Roland E; Bolmont, Tristan; Prokop, Stefan; Winkelmann, Georg; Kaeser, Stephan A; Odenthal, Jorg; Radde, Rebecca; Eldh, Therese; Gandy, Sam; Aguzzi, Adriano; Staufenbiel, Matthias; Mathews, Paul M; Wolburg, Hartwig; Heppner, Frank L; Jucker, Mathias
2009 Nov;12(11):1361-1363, Nature neuroscience
In Alzheimer's disease, microglia cluster around beta-amyloid deposits, suggesting that these cells are important for amyloid plaque formation, maintenance and/or clearance. We crossed two distinct APP transgenic mouse strains with CD11b-HSVTK mice, in which nearly complete ablation of microglia was achieved for up to 4 weeks after ganciclovir application. Neither amyloid plaque formation and maintenance nor amyloid-associated neuritic dystrophy depended on the presence of microglia
— id: 139850, year: 2009, vol: 12, page: 1361, stat: Journal Article,

Complexes of amyloid-beta and cystatin C in the human central nervous system
Mi, Weiqian; Jung, Sonia S; Yu, Haung; Schmidt, Stephen D; Nixon, Ralph A; Mathews, Paul M; Tagliavini, Fabrizio; Levy, Efrat
2009 ;18(2):273-280, Journal of Alzheimer's Disease
A role for cystatin C (CysC) in the pathogenesis of Alzheimer's disease (AD) has been suggested by the genetic linkage of a CysC gene (CST3) polymorphism with late-onset AD, the co-localization of CysC with amyloid-beta (Abeta) in AD brains, and binding of CysC to soluble Abeta in vitro and in mouse models of AD. This study investigates the binding between Abeta and CysC in the human central nervous system. While CysC binding to soluble Abeta was observed in AD patients and controls, a SDS-resistant CysC/Abeta complex was detected exclusively in brains of neuropathologically normal controls, but not in AD cases. The association of CysC with Abeta in brain from control individuals and in cerebrospinal fluid reveals an interaction of these two polypeptides in their soluble form. The association between Abeta and CysC prevented Abeta accumulation and fibrillogenesis in experimental systems, arguing that CysC plays a protective role in the pathogenesis of AD in humans and explains why decreases in CysC concentration caused by the CST3 polymorphism or by specific presenilin 2 mutations can lead to the development of the disease. Thus, enhancing CysC expression or modulating CysC binding to Abeta have important disease-modifying effects, suggesting a novel therapeutic intervention for AD
— id: 126494, year: 2009, vol: 18, page: 273, stat: Journal Article,

In vivo turnover of tau and APP metabolites in the brains of wild-type and Tg2576 mice: greater stability of sAPP in the beta-amyloid depositing mice
Morales-Corraliza, Jose; Mazzella, Matthew J; Berger, Jason D; Diaz, Nicole S; Choi, Jennifer H K; Levy, Efrat; Matsuoka, Yasuji; Planel, Emmanuel; Mathews, Paul M
2009 ;4(9):e7134-e7134, PLoS ONE
The metabolism of the amyloid precursor protein (APP) and tau are central to the pathobiology of Alzheimer's disease (AD). We have examined the in vivo turnover of APP, secreted APP (sAPP), Abeta and tau in the wild-type and Tg2576 mouse brain using cycloheximide to block protein synthesis. In spite of overexpression of APP in the Tg2576 mouse, APP is rapidly degraded, similar to the rapid turnover of the endogenous protein in the wild-type mouse. sAPP is cleared from the brain more slowly, particularly in the Tg2576 model where the half-life of both the endogenous murine and transgene-derived human sAPP is nearly doubled compared to wild-type mice. The important Abeta degrading enzymes neprilysin and IDE were found to be highly stable in the brain, and soluble Abeta40 and Abeta42 levels in both wild-type and Tg2576 mice rapidly declined following the depletion of APP. The cytoskeletal-associated protein tau was found to be highly stable in both wild-type and Tg2576 mice. Our findings unexpectedly show that of these various AD-relevant protein metabolites, sAPP turnover in the brain is the most different when comparing a wild-type mouse and a beta-amyloid depositing, APP overexpressing transgenic model. Given the neurotrophic roles attributed to sAPP, the enhanced stability of sAPP in the beta-amyloid depositing Tg2576 mice may represent a neuroprotective response
— id: 106444, year: 2009, vol: 4, page: e7134, stat: Journal Article,

The in vivo brain interactome of the amyloid precursor protein
Bai, Yu; Markham, Kelly; Chen, Fusheng; Weerasekera, Rasanjala; Watts, Joel; Horne, Patrick; Wakutani, Yosuke; Bagshaw, Rick; Mathews, Paul M; Fraser, Paul E; Westaway, David; St George-Hyslop, Peter; Schmitt-Ulms, Gerold
2008 Jan;7(1):15-34, Molecular & cellular proteomics
Despite intense research efforts, the physiological function and molecular environment of the amyloid precursor protein has remained enigmatic. Here we describe the application of time-controlled transcardiac perfusion cross-linking, a method for the in vivo mapping of protein interactions in intact tissue, to study the interactome of the amyloid precursor protein (APP). To gain insights into the specificity of reported protein interactions the study was extended to the mammalian amyloid precursor-like proteins (APLP1 and APLP2). To rule out sampling bias as an explanation for differences in the individual datasets, a small scale quantitative iTRAQ (isobaric tags for relative and absolute quantitation)-based comparison of APP, APLP1, and APLP2 interactomes was carried out. An interactome map was derived that confirmed eight previously reported interactions of APP and revealed the identity of more than 30 additional proteins that reside in spatial proximity to APP in the brain. Subsequent validation studies confirmed a physiological interaction between APP and leucine-rich repeat and Ig domain-containing protein 1, demonstrated a strong influence of Ig domain-containing protein 1 on the proteolytic processing of APP, and consolidated similarities in the biology of APP and p75
— id: 95390, year: 2008, vol: 7, page: 15, stat: Journal Article,

Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects
Cataldo, Anne M; Mathews, Paul M; Boiteau, Anne Boyer; Hassinger, Linda C; Peterhoff, Corrinne M; Jiang, Ying; Mullaney, Kerry; Neve, Rachael L; Gruenberg, Jean; Nixon, Ralph A
2008 Aug;173(2):370-384, American journal of pathology
Endocytic dysfunction is an early pathological change in Alzheimer's disease (AD) and Down's syndrome (DS). Using primary fibroblasts from DS individuals, we explored the interactions among endocytic compartments that are altered in AD and assessed their functional consequences in AD pathogenesis. We found that, like neurons in both AD and DS brains, DS fibroblasts exhibit increased endocytic uptake, fusion, and recycling, and trafficking of lysosomal hydrolases to rab5-positive early endosomes. Moreover, late endosomes identified using antibodies to rab7 and lysobisphosphatidic acid increased in number and appeared as enlarged, perinuclear vacuoles, resembling those in neurons of both AD and DS brains. In control fibroblasts, similar enlargement of rab5-, rab7-, and lysobisphosphatidic acid-positive endosomes was induced when endocytosis and endosomal fusion were increased by expression of either a rab5 or an active rab5 mutant, suggesting that persistent endocytic activation results in late endocytic dysfunction. Conversely, expression of a rab5 mutant that inhibits endocytic uptake reversed early and late endosomal abnormalities in DS fibroblasts. Our results indicate that DS fibroblasts recapitulate the neuronal endocytic dysfunction of AD and DS, suggesting that increased trafficking from early endosomes can account, in part, for downstream endocytic perturbations that occur in neurons in both AD and DS brains
— id: 95387, year: 2008, vol: 173, page: 370, stat: Journal Article,

Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease
Trinchese, Fabrizio; Fa', Mauro; Liu, Shumin; Zhang, Hong; Hidalgo, Ariel; Schmidt, Stephen D; Yamaguchi, Hisako; Yoshii, Narihiko; Mathews, Paul M; Nixon, Ralph A; Arancio, Ottavio
2008 Aug;118(8):2796-2807, Journal of clinical investigation
Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here we show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD
— id: 95386, year: 2008, vol: 118, page: 2796, stat: Journal Article,

Dysregulation of brain APP in the Ts65Dn Down syndrome mouse
Choi, JH; Mazzella, MJ; Berger, JD; Cataldo, AM; Ginsberg, SD; Levy, E; Nixon, RA; Mathews, PM
2007 AUG ;102(3):131-131, Journal of neurochemistry
— id: 74183, year: 2007, vol: 102, page: 131, stat: Journal Article,

Modulation of Abeta generation by small ubiquitin-like modifiers does not require conjugation to target proteins
Dorval, Veronique; Mazzella, Matthew J; Mathews, Paul M; Hay, Ronald T; Fraser, Paul E
2007 Jun 1;404(2):309-316, Biochemical journal
The sequential processing of the APP (amyloid precursor protein) by the beta- and gamma-secretase and generation of the Abeta (amyloid-beta) peptide is a primary pathological factor in AD (Alzheimer's disease). Regulation of the processing or turnover of these proteins represents potential targets for the development of AD therapies. Sumoylation is a process by which SUMOs (small ubiquitin-like modifiers) are covalently conjugated to target proteins, resulting in a number of functional consequences. These include regulation of protein-protein interactions, intracellular trafficking and protein stability, which all have the potential to impact on several aspects of the amyloidogenic pathway. The present study examines the effects of overexpression and knockdown of the major SUMO isoforms (SUMO1, 2 and 3) on APP processing and the production of Abeta peptides. SUMO3 overexpression significantly increased Abeta40 and Abeta42 secretion, which was accompanied by an increase in full-length APP and its C-terminal fragments. These effects of SUMO3 were independent of its covalent attachment or chain formation, as mutants lacking the motifs responsible for SUMO chain formation or SUMO conjugation led to similar changes in Abeta. SUMO3 overexpression also up-regulated the expression of the transmembrane protease BACE (beta-amyloid-cleaving enzyme), but failed to affect levels of several other unrelated proteins. Suppression of SUMO1 or combined SUMO2+3 by RNA interference did not affect APP levels or Abeta production. These findings confirm a specific effect of SUMO3 overexpression on APP processing and the production of Abeta peptides but also suggest that endogenous sumoylation is not essential and likely plays an indirect role in modulating the amyloid processing pathway
— id: 95392, year: 2007, vol: 404, page: 309, stat: Journal Article,

Elevated plasma cholesterol does not affect brain Abeta in mice lacking the low-density lipoprotein receptor
Elder, Gregory A; Cho, Julie Y; English, Daniel F; Franciosi, Sonia; Schmeidler, James; Sosa, Miguel A Gama; Gasperi, Rita De; Fisher, Edward A; Mathews, Paul M; Haroutunian, Vahram; Buxbaum, Joseph D
2007 Aug;102(4):1220-1231, Journal of neurochemistry
Epidemiological studies support an association between vascular risk factors, including hypercholesterolemia, and Alzheimer's disease (AD). Recently, there has been much interest in the possibility that hypercholesterolemia might directly promote beta-amyloid (Abeta) production. Indeed, in vitro studies have shown that increasing cellular cholesterol levels enhances Abeta production. However, studies in AD transgenic mouse models have not consistently found that elevated plasma cholesterol leads to increased Abeta production or deposition in vivo. In this study, we determined whether elevated peripheral cholesterol influences Abeta production in mice with a null mutation of the low-density lipoprotein receptor (LDLR). We show that dramatically elevated plasma cholesterol levels, whether induced by high cholesterol, high fat, or high fat/high cholesterol diets, did not affect either levels of brain Abeta40, Abeta42, or APP, or the Abeta42/40 or APP-CTF/APP ratios, nor substantially alter brain cholesterol levels. ApoE protein levels in brain were, however, elevated, in LDLR-/- mice by post-transcriptional mechanisms. Collectively, these studies argue that plasma cholesterol levels do not normally regulate production of brain Abeta
— id: 73883, year: 2007, vol: 102, page: 1220, stat: Journal Article,

Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo (vol 102, pg 619, 2007)
Gandy, S; Zhang, YW; Ikin, A; Schmidt, SD; Bogush, A; Levy, E; Sheffield, R; Nixon, RA; Liao, FF; Mathews, PM; Xu, HX; Ehrlich, ME
2007 NOV ;103(3):1272-1272, Journal of neurochemistry
— id: 74687, year: 2007, vol: 103, page: 1272, stat: Journal Article,

Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo
Gandy, Sam; Zhang, Yun-wu; Ikin, Annat; Schmidt, Stephen D; Bogush, Alexey; Levy, Efrat; Sheffield, Roxanne; Nixon, Ralph A; Liao, Francesca-Fang; Mathews, Paul M; Xu, Huaxi; Ehrlich, Michelle E
2007 Aug;102(3):619-626, Journal of neurochemistry
Studies in continuously cultured cells have established that familial Alzheimer's disease (FAD) mutant presenilin 1 (PS1) delays exit of the amyloid precursor protein (APP) from the trans-Golgi network (TGN). Here we report the first description of PS1-regulated APP trafficking in cerebral neurons in culture and in vivo. Using neurons from transgenic mice or a cell-free APP transport vesicle biogenesis system derived from the TGN of those neurons, we demonstrated that knocking-in an FAD-associated mutant PS1 transgene was associated with delayed kinetics of APP arrival at the cell surface. Apparently, this delay was at least partially attributable to impaired exit of APP from the TGN, which was documented in the cell-free APP transport vesicle biogenesis assay. To extend the study to APP and carboxyl terminal fragment (CTF) trafficking to cerebral neurons in vivo, we performed subcellular fractionation of brains from APP transgenic mice, some of which carried a second transgene encoding an FAD-associated mutant form of PS1. The presence of the FAD mutant PS1 was associated with a slight shift in the subcellular localization of both holoAPP and APP CTFs toward iodixanol density gradient fractions that were enriched in a marker for the TGN. In a parallel set of experiments, we used an APP : furin chimeric protein strategy to test the effect of artificially forcing TGN concentration of an APP : furin chimera that could be a substrate for beta- and gamma-cleavage. This chimeric substrate generated excess Abeta42 when compared with wildtype APP. These data indicate that the presence of an FAD-associated mutant human PS1 transgene is associated with redistribution of the APP and APP CTFs in brain neurons toward TGN-enriched fractions. The chimera experiment suggests that TGN-enrichment of a beta-/gamma-secretase substrate may play an integral role in the action of mutant PS1 to elevate brain levels of Abeta42
— id: 95391, year: 2007, vol: 102, page: 619, stat: Journal Article,

Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models
Mi, Weiqian; Pawlik, Monika; Sastre, Magdalena; Jung, Sonia S; Radvinsky, David S; Klein, Andrew M; Sommer, John; Schmidt, Stephen D; Nixon, Ralph A; Mathews, Paul M; Levy, Efrat
2007 Dec;39(12):1440-1442, Nature genetics
Using transgenic mice expressing human cystatin C (encoded by CST3), we show that cystatin C binds soluble amyloid-beta peptide and inhibits cerebral amyloid deposition in amyloid-beta precursor protein (APP) transgenic mice. Cystatin C expression twice that of the endogenous mouse cystatin C was sufficient to substantially diminish amyloid-beta deposition. Thus, cystatin C has a protective role in Alzheimer's disease pathogenesis, and modulation of cystatin C concentrations may have therapeutic implications for the disease
— id: 95389, year: 2007, vol: 39, page: 1440, stat: Journal Article,

Endosome function and pathology in Alzheimer's disease
Cataldo, AM; Mathews, PM; Peterhoff, CM; Boyer-Boiteau, A; Jiang, Y; Nixon, RA
2006 MAR ;96(1):71-71, Journal of neurochemistry
— id: 62904, year: 2006, vol: 96, page: 71, stat: Journal Article,

Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host
Meyer-Luehmann, Melanie; Coomaraswamy, Janaky; Bolmont, Tristan; Kaeser, Stephan; Schaefer, Claudia; Kilger, Ellen; Neuenschwander, Anton; Abramowski, Dorothee; Frey, Peter; Jaton, Anneliese L; Vigouret, Jean-Marie; Paganetti, Paolo; Walsh, Dominic M; Mathews, Paul M; Ghiso, Jorge; Staufenbiel, Matthias; Walker, Lary C; Jucker, Mathias
2006 Sep 22;313(5794):1781-1784, Science
Protein aggregation is an established pathogenic mechanism in Alzheimer's disease, but little is known about the initiation of this process in vivo. Intracerebral injection of dilute, amyloid-beta (Abeta)-containing brain extracts from humans with Alzheimer's disease or beta-amyloid precursor protein (APP) transgenic mice induced cerebral beta-amyloidosis and associated pathology in APP transgenic mice in a time- and concentration-dependent manner. The seeding activity of brain extracts was reduced or abolished by Abeta immunodepletion, protein denaturation, or by Abeta immunization of the host. The phenotype of the exogenously induced amyloidosis depended on both the host and the source of the agent, suggesting the existence of polymorphic Abeta strains with varying biological activities reminiscent of prion strains
— id: 81091, year: 2006, vol: 313, page: 1781, stat: Journal Article,

Endosome dysfunction in Alzheimer's disease: Genetic links and implications for synapse failure and neurodegeneration
Nixon, RA; Cataldo, A; Mathews, P; Jiang, Y; Ginsberg, SD; Peterhoff, C
2006 DEC ;31(2):S28-S28, Neuropsychopharmacology
— id: 70911, year: 2006, vol: 31, page: S28, stat: Journal Article,

Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology
Radde, Rebecca; Bolmont, Tristan; Kaeser, Stephan A; Coomaraswamy, Janaky; Lindau, Dennis; Stoltze, Lars; Calhoun, Michael E; Jaggi, Fabienne; Wolburg, Hartwig; Gengler, Simon; Haass, Christian; Ghetti, Bernardino; Czech, Christian; Holscher, Christian; Mathews, Paul M; Jucker, Mathias
2006 Sep;7(9):940-946, EMBO reports
We have generated a novel transgenic mouse model on a C57BL/6J genetic background that coexpresses KM670/671NL mutated amyloid precursor protein and L166P mutated presenilin 1 under the control of a neuron-specific Thy1 promoter element (APPPS1 mice). Cerebral amyloidosis starts at 6-8 weeks and the ratio of human amyloid (A)beta42 to Abeta40 is 1.5 and 5 in pre-depositing and amyloid-depositing mice, respectively. Consistent with this ratio, extensive congophilic parenchymal amyloid but minimal amyloid angiopathy is observed. Amyloid-associated pathologies include dystrophic synaptic boutons, hyperphosphorylated tau-positive neuritic structures and robust gliosis, with neocortical microglia number increasing threefold from 1 to 8 months of age. Global neocortical neuron loss is not apparent up to 8 months of age, but local neuron loss in the dentate gyrus is observed. Because of the early onset of amyloid lesions, the defined genetic background of the model and the facile breeding characteristics, APPPS1 mice are well suited for studying therapeutic strategies and the pathomechanism of amyloidosis by cross-breeding to other genetically engineered mouse models
— id: 95394, year: 2006, vol: 7, page: 940, stat: Journal Article,

Physiological mouse brain Abeta levels are not related to the phosphorylation state of threonine-668 of Alzheimer's APP
Sano, Yoshitake; Nakaya, Tadashi; Pedrini, Steve; Takeda, Shizu; Iijima-Ando, Kanae; Iijima, Koichi; Mathews, Paul M; Itohara, Shigeyoshi; Gandy, Sam; Suzuki, Toshiharu
2006 ;1:e51-e51, PLoS ONE
BACKGROUND: Amyloid-beta peptide species ending at positions 40 and 42 (Abeta40, Abeta42) are generated by the proteolytic processing of the Alzheimer's amyloid precursor protein (APP). Abeta peptides accumulate in the brain early in the course of Alzheimer's disease (AD), especially Abeta42. The cytoplasmic domain of APP regulates intracellular trafficking and metabolism of APP and its carboxyl-terminal fragments (CTFalpha, CTFbeta). The role of protein phosphorylation in general, and that of the phosphorylation state of APP at threonine-668 (Thr668) in particular, has been investigated in detail by several laboratories (including our own). Some investigators have recently proposed that the phosphorylation state of Thr668 plays a pivotal role in governing brain Abeta levels, prompting the current study. METHODOLOGY: In order to evaluate whether the phosphorylation state of Thr668 controlled brain Abeta levels, we studied the levels and subcellular distributions of holoAPP, sAPPalpha, sAPPbeta, CTFalpha, CTFbeta, Abeta40 and Abeta42 in brains from 'knock-in' mice in which a non-phosphorylatable alanyl residue had been substituted at position 668, replacing the threonyl residue present in the wild-type protein. CONCLUSIONS: The levels and subcellular distributions of holoAPP, sAPPalpha, sAPPbeta, CTFalpha, CTFbeta, Abeta40 and Abeta42 in the brains of Thr668Ala mutant mice were identical to those observed in wild-type mice. These results indicate that, despite speculation to the contrary, the phosphorylation state of APP at Thr668 does not play an obvious role in governing the physiological levels of brain Abeta40 or Abeta42 in vivo
— id: 95393, year: 2006, vol: 1, page: e51, stat: Journal Article,

Targeting the role of the endosome in the pathophysiology of Alzheimer's disease: a strategy for treatment
Tate, Barbara A; Mathews, Paul M
2006 May 25;2006(10):re2-re2, Science of aging knowledge environment
Membrane-bound endosomal vesicles play an integral role in multiple cellular events, including protein processing and turnover, and often critically regulate the cell-surface availability of receptors and other plasma membrane proteins in many different cell types. Neurons are no exception, being dependent on endosomal function for housekeeping and synaptic events. Growing evidence suggests a link between neuronal endosomal function and Alzheimer's disease (AD) pathophysiology. Endosomal abnormalities invariably occur within neurons in AD brains, and endocytic compartments are one likely site for the production of the pathogenic beta-amyloid peptide (Abeta), which accumulates within the brain during the disease and is generated by proteolytic processing of the amyloid precursor protein (APP). The enzymes and events involved in APP processing are appealing targets for therapeutic agents aimed at slowing or reversing the pathogenesis of AD. The neuronal endosome may well prove to be the intracellular site of action for inhibitors of beta-amyloidogenic APP processing. We present here the view that knowledge of the endosomal system in the disease can guide drug discovery of AD therapeutic agents
— id: 95395, year: 2006, vol: 2006, page: re2, stat: Journal Article,

Deficiency in neuronal TGF-beta signaling promotes neurodegeneratbn and Alzheimer's pathology
Tesseur, I; Zou, K; Esposito, L; Bard, F; Berber, E; Van Can, J; Lin, AH; Crews, L; Tremblay, P; Mathews, P; Mucke, L; Masliah, E; Wyss-Coray, T
2006 NOV ;116(11):3060-3069, Journal of clinical investigation
Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cerebral accumulation of the P-amyloid peptide (A beta), but it is unknown what makes neurons susceptible to degeneration. We report that the TGF-beta type II receptor (T beta RII) is mainly expressed by neurons, and that T beta RII levels are reduced in human AD brain and correlate with pathological hallmarks of the disease. Reducing neuronal TGF-beta signaling in mice resulted in age-dependent neurodegeneration and promoted A beta accumulation and dendritic loss in a mouse model of AD. In cultured cells, reduced TGF-beta signaling caused neuronal degeneration and resulted in increased levels of secreted A beta and beta-secretase-cleaved soluble amyloid precursor protein. These results show that reduced neuronal TGF-beta signaling increases age-dependent neurodegeneration and AD-like disease in vivo Increasing neuronal TGF-beta signaling may thus reduce neurodegeneration and be beneficial in AD
— id: 69257, year: 2006, vol: 116, page: 3060, stat: Journal Article,

Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases
Mastrangelo, Peter; Mathews, Paul M; Chishti, M Azhar; Schmidt, Stephen D; Gu, Yongjun; Yang, Jing; Mazzella, Matthew J; Coomaraswamy, Janaky; Horne, Patrick; Strome, Bob; Pelly, Heather; Levesque, Georges; Ebeling, Chris; Jiang, Ying; Nixon, Ralph A; Rozmahel, Richard; Fraser, Paul E; St George-Hyslop, Peter; Carlson, George A; Westaway, David
2005 Jun 21;102(25):8972-8977, Proceedings of the National Academy of Sciences of the United States of America
Gamma-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-beta precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PS1 or PS2 genes shift APP cleavage from production of amyloid-beta (Abeta) 40 peptide to greater production of Abeta42. Although studies in PS1/PS2-deficient embryonic cells define overlapping activities for these proteins, in vivo complementation of PS1-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PS1 transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little Abeta40 or Abeta42 production, and FAD PS2 alleles support robust production of only Abeta42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a 'gained' competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against gamma-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct gamma-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates
— id: 95396, year: 2005, vol: 102, page: 8972, stat: Journal Article,

Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease
Yu, W Haung; Cuervo, Ana Maria; Kumar, Asok; Peterhoff, Corrinne M; Schmidt, Stephen D; Lee, Ju-Hyun; Mohan, Panaiyur S; Mercken, Marc; Farmery, Mark R; Tjernberg, Lars O; Jiang, Ying; Duff, Karen; Uchiyama, Yasuo; Naslund, Jan; Mathews, Paul M; Cataldo, Anne M; Nixon, Ralph A
2005 Oct 10;171(1):87-98, Journal of cell biology
Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before beta-amyloid (Abeta) deposits extracellularly in the presenilin (PS) 1/Abeta precursor protein (APP) mouse model of beta-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Abeta. Purified AVs contain APP and beta-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent gamma-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Abeta production. Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD
— id: 60255, year: 2005, vol: 171, page: 87, stat: Journal Article,

Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology
Cataldo, Anne M; Peterhoff, Corrinne M; Schmidt, Stephen D; Terio, Nicole B; Duff, Karen; Beard, Margaret; Mathews, Paul M; Nixon, Ralph A
2004 Aug;63(8):821-830, Journal of neuropathology & experimental neurology
The neuronal lysosomal system is a major degradative pathway, induced by cell stress and closely linked to Alzheimer disease (AD) and other neurodegenerative diseases. Here, we show that mutations of presenilin (PS) 1 and 2, which cause familial early-onset AD (FAD), induce more severe lysosomal system neuropathology in humans than does sporadic AD (SAD). Cathepsin D and B levels were higher in PS-FAD neocortex than in SAD and, unlike neurons in SAD, expressed higher levels of the cation-independent mannose-6-phosphate receptor. Lysosomal pathology was also evident in more populations of neurons in PS-FAD brains, including the less vulnerable neurons in laminae II and IV and affected neurons contained high numbers of hydrolase-positive vesicular compartments with a broader range of abnormal morphology. In transgenic mice expressing mutant amyloid precursor protein (APPswe), introducing mutant PSI significantly upregulated the lysosomal system in neocortical and hippocampal neurons. This upregulation, though milder in severity, resembled that seen in human PS-FAD. Accumulation of hydrolases in dystrophic neurites in senile plaques was particularly strong, suggesting that amyloid deposition may be a stimulus for local mobilization of the lysosomal system. PS1 mice lacking the APPswe transgene also had a mild lysosomal response in some neuronal populations, which was not seen in the APPswe mice. Our findings suggest that presenilin mutations have amyloid-independent effects on the lysosomal system, which are synergistic with the lysosomal system pathology that is associated with beta-amyloid
— id: 95397, year: 2004, vol: 63, page: 821, stat: Journal Article,

Both the sequence and length of the C terminus of PEN-2 are critical for intermolecular interactions and function of presenilin complexes
Hasegawa, Hiroshi; Sanjo, Nobuo; Chen, Fusheng; Gu, Yong-Jun; Shier, Cortney; Petit, Agnes; Kawarai, Toshitaka; Katayama, Taiichi; Schmidt, Stephen D; Mathews, Paul M; Schmitt-Ulms, Gerold; Fraser, Paul E; St George-Hyslop, Peter
2004 Nov 5;279(45):46455-46463, Journal of biological chemistry
Presenilin 1 or presenilin 2, nicastrin, APH-1, and PEN-2 form high molecular weight complexes that play a pivotal role in the cleavage of various Type I transmembrane proteins, including the beta-amyloid precursor protein. The specific function of PEN-2 is unclear. To explore its function and intermolecular interactions, we conducted deletion and mutagenesis studies on a series of conserved residues at the C terminus of PEN-2. These studies suggest that: 1) both the presence and amino acid sequence of the conserved DYLSF domain at the C terminus of PEN-2 (residues 90-94) is critical for binding PEN-2 to other components in the presenilin complex and 2) the overall length of the exposed C terminus is critical for functional gamma-secretase activity
— id: 95398, year: 2004, vol: 279, page: 46455, stat: Journal Article,

Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis
Herzig, Martin C; Winkler, David T; Burgermeister, Patrick; Pfeifer, Michelle; Kohler, Esther; Schmidt, Stephen D; Danner, Simone; Abramowski, Dorothee; Sturchler-Pierrat, Christine; Burki, Kurt; van Duinen, Sjoerd G; Maat-Schieman, Marion L C; Staufenbiel, Matthias; Mathews, Paul M; Jucker, Mathias
2004 Sep;7(9):954-960, Nature neuroscience
The E693Q mutation in the amyloid beta precursor protein (APP) leads to cerebral amyloid angiopathy (CAA), with recurrent cerebral hemorrhagic strokes and dementia. In contrast to Alzheimer disease (AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) show few parenchymal amyloid plaques. We found that neuronal overexpression of human E693Q APP in mice (APPDutch mice) caused extensive CAA, smooth muscle cell degeneration, hemorrhages and neuroinflammation. In contrast, overexpression of human wild-type APP (APPwt mice) resulted in predominantly parenchymal amyloidosis, similar to that seen in AD. In APPDutch mice and HCHWA-D human brain, the ratio of the amyloid-beta40 peptide (Abeta40) to Abeta42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of AbetaDutch40/AbetaDutch42 toward AbetaDutch42 by crossing APPDutch mice with transgenic mice producing mutated presenilin-1 redistributed the amyloid pathology from the vasculature to the parenchyma. The understanding that different Abeta species can drive amyloid pathology in different cerebral compartments has implications for current anti-amyloid therapeutic strategies. This HCHWA-D mouse model is the first to develop robust CAA in the absence of parenchymal amyloid, highlighting the key role of neuronally produced Abeta to vascular amyloid pathology and emphasizing the differing roles of Abeta40 and Abeta42 in vascular and parenchymal amyloid pathology
— id: 95399, year: 2004, vol: 7, page: 954, stat: Journal Article,

Effect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised
Lacombe P; Mathews PM; Schmidt SD; Breidert T; Heneka MT; Landreth GE; Feinstein DL; Galea E
2004 Jul 2;1(1):11-11, Journal of Neuroinflammation
BACKGROUND: The over-expression of transforming growth factor beta-1(TGF-beta1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidbeta (Abeta) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-beta1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-beta1. This idea was in accordance with the view that chronic inflammation contributes to Alzheimer's disease, and drew attention to the therapeutic potential of anti-inflammatory drugs for the treatment of Abeta-elicited CAA. We thus studied the effect of anti-inflammatory drug administration in TGF-beta1-induced pathology. METHODS: Two-month-old TGF-beta1 mice and littermate controls were orally administered pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, or ibuprofen, a non steroidal anti-inflammatory agent, for two months. Glia activation was assessed by immunohistochemistry and western blot analysis; Abeta precursor protein (APP) by western blot analysis; Abeta deposition by immunohistochemistry, thioflavin-S staining and ELISA; and hydrocephalus by measurements of ventricle size on autoradiographies of brain sections. Results are expressed as means +/- SD. Data comparisons were carried with the Student's T test when two groups were compared, or ANOVA analysis when more than three groups were analyzed. RESULTS: Animals displayed glia activation, hydrocephalus and a robust thioflavin-S-positive vascular deposition. Unexpectedly, these deposits contained no Abeta or serum amyloid P component, a common constituent of amyloid deposits. The thioflavin-S-positive material thus remains to be identified. Pioglitazone decreased glia activation and basal levels of Abeta42- with no change in APP contents - while it increased hydrocephalus, and had no effect on the thioflavin-S deposits. Ibuprofen mimicked the reduction of glia activation caused by pioglitazone and the lack of effect on the thioflavin-S-labeled deposits. CONCLUSIONS: i) TGF-beta1 over-expressing mice may not be an appropriate model of Abeta-elicited CAA; and ii) pioglitazone has paradoxical effects on TGF-beta1-induced pathology suggesting that anti-inflammatory therapy may reduce the damage resulting from active glia, but not from vascular alterations or hydrocephalus. Identification of the thioflavin-S-positive material will facilitate the full appraisal of the clinical implication of the effects of anti-inflammatory drugs, and provide a more thorough understanding of TGF-beta1 actions in brain
— id: 61232, year: 2004, vol: 1, page: 11, stat: Journal Article,

Co-expressed presenilin 1 NTF and CTF form functional gamma-secretase complexes in cells devoid of full-length protein
Laudon, Hanna; Mathews, Paul M; Karlstrom, Helena; Bergman, Anna; Farmery, Mark R; Nixon, Ralph A; Winblad, Bengt; Gandy, Samuel E; Lendahl, Urban; Lundkvist, Johan; Naslund, Jan
2004 Apr;89(1):44-53, Journal of neurochemistry
Abstract The enzyme gamma-secretase catalyzes the intramembrane proteolytic cleavage that generates the amyloid beta-peptide from the beta-amyloid precursor protein. The presenilin (PS) protein is one of the four integral membrane protein components of the mature gamma-secretase complex. The PS protein is itself subjected to endoproteolytic processing, generating stable N- and C-terminal fragment (NTF and CTF, respectively) heterodimers. Here we demonstrate that coexpression of PS1 NTF and CTF functionally mimics expression of the full-length PS1 protein and restores gamma-secretase activity in PS-deficient mammalian cells. The coexpressed fragments re-associate with each other inside the cell, where they also interact with nicastrin, another gamma-secretase complex component. Analysis of gamma-secretase activity following the expression of mutant forms of NTF and CTF, under conditions bypassing endoproteolysis, indicated that the putatively catalytic Asp257 and Asp385 residues have a direct effect on gamma-secretase activity. Moreover, we demonstrate that expression of the wild-type CTF rescues endoproteolytic cleavage of C-terminally truncated PS1 molecules that are otherwise uncleaved and inactive. Recovery of cleavage is critically dependent on the integrity of Asp385. Taken together, our findings indicate that ectopically expressed NTF and CTF restore functional gamma-secretase complexes and that the presence of full-length PS1 is not a requirement for proper complex assembly
— id: 42252, year: 2004, vol: 89, page: 44, stat: Journal Article,

Overexpression of human cystatin C in transgenic mice does not affect levels of endogenous brain amyloid Beta Peptide
Pawlik, Monika; Sastre, Magdalena; Calero, Miguel; Mathews, Paul M; Schmidt, Stephen D; Nixon, Ralph A; Levy, Efrat
2004 ;22(1-2):13-18, Journal of molecular neuroscience
Cystatin C, an inhibitor of cysteine proteases, colocalizes with amyloid beta (Abeta) in parenchymal and vascular amyloid deposits in brains of Alzheimer's disease (AD) patients, suggesting that cystatin C has a role in AD. Cystatin C also colocalizes with beta amyloid precursor protein (betaAPP) in transfected cultured cells. In vitro analysis of the association between the two proteins revealed that binding of cystatin C to full-length betaAPP does not affect the level of Abeta secretion. Here we studied the effect of in vivo overexpression of cystatin C on the levels of endogenous brain Abeta. We have generated lines of transgenic mice expressing either wild-type human cystatin C or the Leu68Gln variant that forms amyloid deposits in the cerebral vessels of Icelandic patients with hereditary cerebral hemorrhage, under control sequences of the human cystatin C gene. Western blot analysis of brain homogenates was used to select lines of mice expressing various levels of the transgene. Analysis of Abeta40 and Abeta42 concentrations in the brain showed no difference between transgenic mice and their nontransgenic littermates. Thus, in vivo overexpression of human cystatin C does not affect Abeta levels in mice that do not deposit Abeta
— id: 42253, year: 2004, vol: 22, page: 13, stat: Journal Article,

Cerebral hemorrhage and amyloid-beta
Atwood, Craig S; Perry, George; Smith, Mark A
2003 Feb 14;299(5609):1014-1014, Science
— id: 34107, year: 2003, vol: 299, page: 1014, stat: Journal Article,

Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo
Burns, Mark; Gaynor, Kate; Olm, Vicki; Mercken, Marc; LaFrancois, John; Wang, Lili; Mathews, Paul M; Noble, Wendy; Matsuoka, Yasuji; Duff, Karen
2003 Jul 2;23(13):5645-5649, Journal of neuroscience
Epidemiology, in vitro, and in vivo studies strongly implicate a role for cholesterol in the pathogenesis of Alzheimer's disease (AD). We have examined the impact of aberrant intracellular cholesterol transport on the processing of the amyloid precursor protein (APP) in a mouse model of Niemann-Pick type C (NPC) disease. In the NPC mouse brain, cholesterol accumulates in late endosomes/lysosomes. This was associated with the accumulation of beta-C-terminal fragments (CTFs) of APP, but the level of beta-secretase and its activity were not affected. Alpha-secretase activity and secreted APPalpha generation were also not affected, suggesting CTFs increased because of decreased clearance. The level of presenilin-1 (PS-1) was unchanged, but gamma-secretase activity was greatly enhanced, which correlated with an increase in Abeta40 and Abeta42 levels. These events were associated with abnormal distribution of PS-1 in the endosomal system. Our results show that aberrant cholesterol trafficking is associated with the potentiation of APP processing components in vivo, leading to an overall increase in Abeta levels
— id: 36834, year: 2003, vol: 23, page: 5645, stat: Journal Article,

Extracellular amyloid formation and associated pathology in neural grafts
Meyer-Luehmann, Melanie; Stalder, Martina; Herzig, Martin C; Kaeser, Stephan A; Kohler, Esther; Pfeifer, Michelle; Boncristiano, Sonia; Mathews, Paul M; Mercken, Marc; Abramowski, Dorothee; Staufenbiel, Matthias; Jucker, Mathias
2003 Apr;6(4):370-377, Nature neuroscience
Amyloid precursor protein (APP) processing and the generation of beta-amyloid peptide (Abeta) are important in the pathogenesis of Alzheimer's disease. Although this has been studied extensively at the molecular and cellular levels, much less is known about the mechanisms of amyloid accumulation in vivo. We transplanted transgenic APP23 and wild-type B6 embryonic neural cells into the neocortex and hippocampus of both B6 and APP23 mice. APP23 grafts into wild-type hosts did not develop amyloid deposits up to 20 months after grafting. In contrast, both transgenic and wild-type grafts into young transgenic hosts developed amyloid plaques as early as 3 months after grafting. Although largely diffuse in nature, some of the amyloid deposits in wild-type grafts were congophilic and were surrounded by neuritic changes and gliosis, similar to the amyloid-associated pathology previously described in APP23 mice. Our results indicate that diffusion of soluble Abeta in the extracellular space is involved in the spread of Abeta pathology, and that extracellular amyloid formation can lead to neurodegeneration
— id: 34106, year: 2003, vol: 6, page: 370, stat: Journal Article,

In vivo reduction of amyloid-{beta} by a mutant copper transporter
Phinney, Amie L; Drisaldi, Bettina; Schmidt, Stephen D; Lugowski, Stan; Coronado, Veronica; Liang, Yan; Horne, Patrick; Yang, Jing; Sekoulidis, Joannis; Coomaraswamy, Janaky; Chishti, M Azhar; Cox, Diane W; Mathews, Paul M; Nixon, Ralph A; Carlson, George A; St George-Hyslop, Peter; Westaway, David
2003 Nov 25;100(24):14193-14198, Proceedings of the National Academy of Sciences of the United States of America
Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-beta (Abeta) peptide. To explore this relationship in vivo, toxic-milk (txJ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust Abeta deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive txJ mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma Abeta levels. In addition, homozygosity for txJ increased survival of young TgCRND8 mice and lowered endogenous CNS Abeta at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the txJ mutation on CNS Abeta burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Abeta peptide
— id: 40065, year: 2003, vol: 100, page: 14193, stat: Journal Article,

Rab5 overexpression in a cell model of AD-related endocytic abnormalities influences processing of beta APP
Grbovic, OM; Schmidt, SD; Mathews, PM; Nixon, RA; Cataldo, AM
2002 Jul-Aug;23(1):50-, Neurobiology of aging
— id: 32405, year: 2002, vol: 23, page: 50, stat: Journal Article,

Quantitation of beta-cleaved carboxy-terminal fragments of APP with a novel ELISA
Jiang, Y; Schmidt, SD; Mercken, M; Mathews, PM; Nixon, RA
2002 Jul-Aug;23(1):62-, Neurobiology of aging
— id: 32406, year: 2002, vol: 23, page: 62, stat: Journal Article,

Calpain Activity Regulates the Cell Surface Distribution of Amyloid Precursor Protein. INHIBITION OF CALPAINS ENHANCES ENDOSOMAL GENERATION OF beta -CLEAVED C-TERMINAL APP FRAGMENTS
Mathews, Paul M; Jiang, Ying; Schmidt, Stephen D; Grbovic, Olivera M; Mercken, Marc; Nixon, Ralph A
2002 Sep 27;277(39):36415-36424, Journal of biological chemistry
In murine L cells, treatment with calpeptin or calpain inhibitor III increased Abeta42, but not Abeta40, secretion in a dose-dependent fashion. This correlated with an increase in the levels of amyloid precursor protein (APP) carboxyl-terminal fragments (CTFs). Immunoprecipitation with novel mAbs directed against the carboxyl-terminus of APP or specific for the beta-cleaved CTF showed that generation of both alpha- and beta-cleaved CTFs increase proportionately following inhibition of calpains. Pulse-chase metabolic labeling confirmed that inhibiting calpains increases the production of alpha- and beta-cleaved APP metabolites. Immunolabeling showed greater betaCTF signal in calpeptin-treated cells, primarily in small vesicular compartments that were shown to be predominantly endosomal by colocalization with early endosomal antigen 1. A second mAb, which recognizes an extracellular/luminal epitope found on both APP and betaCTFs, gave more cell surface labeling of calpeptin-treated cells than control cells. Quantitative binding of this antibody confirmed that inhibiting calpains caused a partial redistribution of APP to the cell surface. These results demonstrate that 1) calpain inhibition results in a partial redistribution of APP to the cell surface, 2) this redistribution leads to an increase in both alpha- and beta-cleavage without changing the ratio of alphaCTFs/betaCTFs, and 3) the bulk of the betaCTFs in the cell are within early endosomes, confirming the importance of this compartment in APP processing
— id: 32534, year: 2002, vol: 277, page: 36415, stat: Journal Article,

Altered APP trafficking and a role for the early endosome in increased beta CTF generation following calpain inhibition
Mathews, PM; Nixon, RA; Jiang, Y; Schmidt, SD; Grbovic, OM; Mercken, M; Cataldo, AM
2002 Jul-Aug;23(1):671-, Neurobiology of aging
— id: 32414, year: 2002, vol: 23, page: 671, stat: Journal Article,

Autophagic cell death: Relevance to Alzheimer disease neurodegeneration
Nixon, RA; Mathews, PM; Ginsberg, SD; Duff, K; Mohan, P; Cataldo, AM; Wegiel, J; Yu, WH; Schmidt, SD; Jacobsen, SP; Peterhoff, CM; Terio, N; Keller, JN; Hassinger, L
2002 Jul-Aug;23(1):1527-, Neurobiology of aging
— id: 32429, year: 2002, vol: 23, page: 1527, stat: Journal Article,

Cerebral hemorrhage after passive anti-Abeta immunotherapy
Pfeifer, M; Boncristiano, S; Bondolfi, L; Stalder, A; Deller, T; Staufenbiel, M; Mathews, P M; Jucker, M
2002 Nov 15;298(5597):1379-1379, Science
— id: 32570, year: 2002, vol: 298, page: 1379, stat: Journal Article,

Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype
Rozmahel, Richard; Mount, Howard T J; Chen, Fusheng; Nguyen, Van; Huang, Jean; Erdebil, Serap; Liauw, Jennifer; Yu, Gang; Hasegawa, Hiroshe; Gu, YongJun; Song, You-Qiang; Schmidt, Stephen D; Nixon, Ralph A; Mathews, Paul M; Bergeron, Catherine; Fraser, Paul; Westaway, David; St George-Hyslop, Peter
2002 Oct 29;99(22):14452-14457, Proceedings of the National Academy of Sciences of the United States of America
Presenilin 1 (PS1), presenilin 2, and nicastrin form high molecular weight complexes that are necessary for the endoproteolysis of several type 1 transmembrane proteins, including amyloid precursor protein (APP) and the Notch receptor, by apparently similar mechanisms. The cleavage of the Notch receptor at the 'S3-site' releases a C-terminal cytoplasmic fragment (Notch intracellular domain) that acts as the intracellular transduction molecule for Notch activation. Missense mutations in the presenilins cause familial Alzheimer's disease by augmenting the 'gamma-secretase' cleavage of APP and overproducing one of the proteolytic derivatives, the Abeta peptide. Null mutations in PS1 inhibit both gamma-secretase cleavage of APP and S3-site cleavage of the Notch receptor. Mice lacking PS1 function have defective Notch signaling and die perinatally with severe skeletal and brain deformities. We report here that a genetic modifier on mouse distal chromosome 1, coinciding with the locus containing Nicastrin, influences presenilin-mediated Notch S3-site cleavage and the resultant Notch phenotype without affecting presenilin-mediated APP gamma-site cleavage. Two missense substitutions of residues conserved among vertebrates have been identified in nicastrin. These results indicate that Notch S3-site cleavage and APP gamma-site cleavage are distinct presenilin-dependent processes and support a functional interaction between nicastrin and presenilins in vertebrates. The dissociation of Notch S3-site and APP gamma-site cleavage activities will facilitate development of gamma-secretase inhibitors for treatment of Alzheimer's disease
— id: 32537, year: 2002, vol: 99, page: 14452, stat: Journal Article,

Murine A beta co-deposition in transgenic mice: Analyses with species-specific antibodies and comparison of human and murine A beta 42 : A beta 40 ratios
Schmidt, S; Jiang, Y; Duff, KEK; Nixon, RA; Mathews, PM; Herzig, MC; Jucker, M; Chishti, MA; Westaway, D; Mercken, M; Staufenbiel, M
2002 Jul-Aug;23(1):920-, Neurobiology of aging
— id: 32422, year: 2002, vol: 23, page: 920, stat: Journal Article,

Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins
Yang, Dun-Sheng; Tandon, Anurag; Chen, Fusheng; Yu, Gang; Yu, Haung; Arawaka, Shigeki; Hasegawa, Hiroshi; Duthie, Monika; Schmidt, Stephen D; Ramabhadran, Triprayer V; Nixon, Ralph A; Mathews, Paul M; Gandy, Samuel E; Mount, Howard T J; St George-Hyslop, Peter; Fraser, Paul E
2002 Aug 2;277(31):28135-28142, Journal of biological chemistry
Nicastrin is an integral component of the high molecular weight presenilin complexes that control proteolytic processing of the amyloid precursor protein and Notch. We report here that nicastrin is most probably a type 1 transmembrane glycoprotein that is expressed at moderate levels in the brain and in cultured neurons. Immunofluorescence studies demonstrate that nicastrin is localized in the endoplasmic reticulum, Golgi, and a discrete population of vesicles. Glycosidase analyses reveal that endogenous nicastrin undergoes a conventional, trafficking-dependent maturation process. However, when highly expressed in transfected cells, there is a disproportionate accumulation of the endo-beta-N-acetylglucosaminidase H-sensitive, immature form, with no significant increase in the levels of the fully mature species. Immunoprecipitation revealed that presenilin-1 interacts preferentially with mature nicastrin, suggesting that correct trafficking and co-localization of the presenilin complex components are essential for activity. These findings demonstrate that trafficking and post-translational modifications of nicastrin are tightly regulated processes that accompany the assembly of the active presenilin complexes that execute gamma-secretase cleavage. These results also underscore the caveat that simple overexpression of nicastrin in transfected cells may result in the accumulation of large amounts of the immature protein, which is apparently unable to assemble into the active complexes capable of processing amyloid precursor protein and Notch
— id: 62376, year: 2002, vol: 277, page: 28135, stat: Journal Article,

Autophagy-dependent generation of the amyloid-beta (A beta) peptide
Yu, WH; Schmidt, SD; Jiang, Y; Mathews, PM; Nixon, RA; Hassinger, L; Cataldo, A
2002 Jul-Aug;23(1):48-, Neurobiology of aging
— id: 32404, year: 2002, vol: 23, page: 48, stat: Journal Article,

Accelerated A-beta generation in a cell model of Alzheimer's disease-related endosomal-lysomal system upregulation
Mathews PM; Guerra CB; Jiang Y; Kao BH; Dinakar R; Mehta P; Cataldo AM; Nixon RA
Alzheimer's disease: advances in etiology, pathogenesis and therapeutics Chichester: Wiley, 2001,
— id: 2653, year: 2001, vol: , page: 461, stat: Chapter,

The neuronal endosomal-lysosomal system in Alzheimer's disease
Nixon RA; Mathews PM; Cataldo AM
2001 Feb;3(1):97-107, Journal of Alzheimer's Disease
Robust activation of the neuronal lysosomal system and cellular pathways converging on the lysosome, such as the endocytic and autophagic pathways, are prominent neuropathological features of Alzheimer's disease. Disturbances of the neuronal endocytic pathway, which are one of the earliest known intracellular changes occurring in Alzheimer's disease and Down syndrome, provide insight into how beta-amyloidogenesis might be promoted in sporadic Alzheimer's disease, the most prevalent and least well understood form of the disease. Primary lysosomal system dysfunction in inherited disorders is commonly associated with prominent neurological phenotypes and neurodegeneration. New studies now directly implicate lysosomal cathepsins as proteases capable of initiating, as well as executing, cell death programs. These and other studies support the view that the progressive alterations of lysosomal system function in Alzheimer's disease have broad relevance to the neurodegenerative processes occurring during the disease
— id: 32538, year: 2001, vol: 3, page: 97, stat: Journal Article,

In vivo perturbation of lysosomal function promotes neurodegeneration in the PS1m146V/APPPK67ON,M671L mouse model of Alzheimer's disease pathology
Nixon RA; Mathews PM; Cataldo AM; Mohan PS; Schmidt SD; Duff K; Berg M; Marks N; Peterhoff C; Sershen H
Alzheimer's disease: advances in etiology, pathogenesis and therapeutics Chichester: Wiley, 2001,
— id: 2654, year: 2001, vol: , page: , stat: Chapter,

Experimental aging of the lysosomal system promotes neurodegeneration in the PS/APP mouse model of Alzheimer's disease pathology
Nixon, R. A.; Mathews, P. M.; Cataldo, A. M.; Mohan, P. S.; Marks, N.; Duff, K.; Berg, M.; Schmidt, S. D.; Jacobsen, S. P.; Jiang, Y.; Sershen, H.
2001 ;27(1):925-925, Abstracts (Society for Neuroscience)
The lysosomal system (LS) is markedly activated in vulnerable neuronal populations early in Alzheimer's disease, although lysosomes become less efficient degradative compartments as neurons become more compromised. LS dysfunction, especially altered activity of the lysosomal protease cathepsin D, has been implicated in cell death initiation under various apoptotic conditions in vivo and in vitro. In this study, we observed that cathepsin D content increases nearly 3-fold in the human neocortex during normal aging while lysosomal cysteine protease activities decrease. By contrast, during aging in the mouse, this protease imbalance and other aging-related changes of the LS, such as lipofuscin accumulation, are minimal in these cortical areas. However, when leupeptin (a cysteine protease inhibitor) was infused intraventricularly, an imbalance of cathepsins similar to that in the aging human brain was induced. This was accompanied by changes associated with cell senescence, including ceroid-lipofuscin accumulation and alterations of tau proteolysis. In PSM146L/APPSWE transgenic mice, super-imposition of this aging-related cathepsin imbalance accentuated preexisting LS abnormalities to the level seen in AD brain and also induced neuronal atrophy and neurodegeneration. The minimal degree of 'lysosomal aging' seen in old mice, compared to that in humans, may partly explain the mild neurodegenerative phenotypes in transgenic models of AD pathology. In addition, these studies provide in vivo evidence relating altered lysosomal function to neurodegeneration
— id: 115690, year: 2001, vol: 27, page: 925, stat: Journal Article,

A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease
Janus C; Pearson J; McLaurin J; Mathews PM; Jiang Y; Schmidt SD; Chishti MA; Horne P; Heslin D; French J; Mount HT; Nixon RA; Mercken M; Bergeron C; Fraser PE; St George-Hyslop P; Westaway D
2000 Dec 21-28;408(6815):979-982, Nature
Much evidence indicates that abnormal processing and extracellular deposition of amyloid-beta peptide (A beta), a proteolytic derivative of the beta-amyloid precursor protein (betaAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with A beta causes a marked reduction in burden of the brain amyloid. Evidence that A beta immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal A beta processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the 'amyloid cascade'. Here we show that A beta immunization reduces both deposition of cerebral fibrillar A beta and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of A beta in the brain. This implies that either a approximately 50% reduction in dense-cored A beta plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic A beta species
— id: 24772, year: 2000, vol: 408, page: 979, stat: Journal Article,

Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease
Mathews PM; Cataldo AM; Kao BH; Rudnicki AG; Qin X; Yang JL; Jiang Y; Picciano M; Hulette C; Lippa CF; Bird TD; Nochlin D; Walter J; Haass C; Levesque L; Fraser PE; Andreadis A; Nixon RA
2000 Oct;6(10):878-891, Molecular medicine
BACKGROUND: Mutations in the presenilin proteins cause early-onset, familial Alzheimer's disease (FAD). MATERIALS AND METHODS: We characterized the cellular localization and endoproteolysis of presenilin 2 (PS2) and presenilin 1 (PS1) in brains from 25 individuals with presenilin-mutations causing FAD, as well as neurologically normal individuals and individuals with sporadic Alzheimer's disease (AD). RESULTS: Amino-terminal antibodies to both presenilins predominantly decorated large neurons. Regional differences between the broad distributions of the two presenilins were greatest in the cerebellum, where most Purkinje cells showed high levels of only PS2 immunoreactivity. PS2 endoproteolysis in brain yielded multiple amino-terminal fragments similar in size to the PS1 amino-terminal fragments detected in brain. In addition, two different PS2 amino-terminal antibodies also detected a prominent 42 kDa band that may represent a novel PS2 form in human brain. Similar to PS1 findings, neither amino-terminal nor antiloop PS2 antibodies revealed substantial full-length PS2 in brain. Immunocytochemical examination of brains from individuals with the N141I PS2 mutation or eight different PS1 mutations, spanning the molecule from the second transmembrane domain to the large cytoplasmic loop domain, revealed immunodecoration of no senile plaques and only neurofibrillary tangles in the M139I PS1 mutation stained with PS1 antibodies. CONCLUSIONS: Overall presenilin expression and the relative abundance of full-length and amino-terminal fragments in presenilin FAD cases were similar to control cases and sporadic AD cases. Thus, accumulation of full-length protein or other gross mismetabolism of neither PS2 nor PS1 is a consequence of the FAD mutations examined
— id: 25504, year: 2000, vol: 6, page: 878, stat: Journal Article,

The endosomal-lysosomal system of neurons in Alzheimer's disease pathogenesis: a review
Nixon RA; Cataldo AM; Mathews PM
2000 Oct;25(9-10):1161-1172, Neurochemical research
A prominent feature of brain pathology in Alzheimer's disease is a robust activation of the neuronal lysosomal system and major cellular pathways converging on the lysosome, namely, endocytosis and autophagy. Recent studies that identify a disturbance of the endocytic pathway as one of the earliest known manifestation of Alzheimer's disease provide insight into how beta-amyloidogenesis might be promoted in sporadic Alzheimer's disease, the most prevalent and least well understood form of the disease. Primary lysosomal dysfunction has historically been linked to neurodegeneration. New data now directly implicate cathepsins as proteases capable of initiating, as well as executing, cell death programs in certain pathologic states. These and other studies support the view that the progressive alterations of lysosomal function observed during aging and Alzheimer's disease contribute importantly to the neurodegenerative process in Alzheimer's disease
— id: 24724, year: 2000, vol: 25, page: 1161, stat: Journal Article,

Developmental expression of wild-type and mutant presenilin-1 in hippocampal neurons from transgenic mice: evidence for novel species-specific properties of human presenilin-1
Levesque L; Annaert W; Craessaerts K; Mathews PM; Seeger M; Nixon RA; Van Leuven F; Gandy S; Westaway D; St George-Hyslop P; De Strooper B; Fraser PE
1999 Aug;5(8):542-554, Molecular medicine
Presenilins 1 (PS1) and 2 (PS2) are multispanning transmembrane proteins associated with familial Alzheimer disease (FAD). They are developmentally regulated, being expressed at highest levels during neuronal differentiation and are sustained at a lower level throughout life. We investigated the distribution and metabolism of endogenous murine PS1 as well as human wild-type (wtPS1) and the familial AD Met146Leu (M146L) mutant presenilins in dissociated cultures of hippocampal neurons derived from control and transgenic mice. We found that the PS1 endoproteolytic fragments and, to a lesser extent, the full-length protein, were expressed as early as day 3 post-plating. Both species increased until the cells were fully differentiated at day 12. Confocal microscopy revealed that presenilin is present in the Golgi and endoplasmic reticulum and, as in punctate, vesicle-like structures within developing neurites and growth cones. Using a human-specific PS1 antibody, we were able to independently examine the distribution of the transgenic protein which, although similar to the endogenous, showed some unique qualities. These included (i) some heterogeneity in the proteolytic fragments of human PS1; (ii) significantly reduced levels of full-length human PS1, possibly as a result of preferential processing; and (iii) a more discrete intracellular distribution of human PS1. Colocalization with organelle-specific proteins revealed that PS1 was located in a diffuse staining pattern in the MAP2-positive dendrites and in a punctate manner in GAP43-positive axons. PS1 showed considerable overlap with GAP43, particularly at the growth cones. Similar patterns of PS1 distribution were detected in cultures derived from transgenic animals expressing human wild-type or mutant presenilins. The studies demonstrate that mutant presenilins are not grossly different in their processing or distribution within cultured neurons, which may represent more physiological models as compared to transfection systems. Our data also suggest that the molecular pathology associated with PS1 mutations results from subtle alterations in presenilin function, which can be further investigated using these transgenic neuronal cell culture models
— id: 24709, year: 1999, vol: 5, page: 542, stat: Journal Article,

Cellular expression and proteolytic processing of presenilin proteins is developmentally regulated during neuronal differentiation
Capell A; Saffrich R; Olivo JC; Meyn L; Walter J; Grunberg J; Mathews P; Nixon R; Dotti C; Haass C
1997 Dec;69(6):2432-2440, Journal of neurochemistry
We have determined the expression of the Alzheimer's disease-associated proteins presenilin-1 and presenilin-2 in primary cultures of rat hippocampal neurons. Neurons highly express presenilin-1 and presenilin-2, whereas both proteins were not detected in astrocytes. Further, we have analyzed the subcellular localization and expression in rat hippocampal neurons during development. Although presenilin proteins were localized predominantly to the endoplasmic reticulum in nonneuronal cells transfected with presenilin cDNAs, in neurons, presenilin proteins were also found in compartments not staining with antibodies to grp78(BiP). Presenilin-1 and presenilin-2 were predominantly detected in vesicular structures within the somatodendritic compartment with much less expression in axons. Polarized distribution of presenilin-1 and presenilin-2 differs slightly, with more presenilin-2 expressed in axons compared with presenilin-1. Presenilin expression was found to be developmentally regulated. Presenilin expression strongly increased during neuronal differentiation until full morphological polarization and then declined. No full-length presenilin-1 or presenilin-2 could be detected within cell lysates. At early developmental stages the expected approximately 34-kDa N-terminal proteolytic fragment of presenilin-1 and the approximately 38-kDa fragment of presenilin-2 were detected. Later during differentiation we predominantly detected a approximately 38-kDa fragment for presenilin-1 and a approximately 42-kDa fragment for presenilin-2. By epitope mapping, we show that these slower migrating peptides represent N-terminal proteolytic fragments, cleaved C-terminal to the conventional site of processing. It is noteworthy that both presenilin-1 and presenilin-2 undergo alternative proteolytic cleavage at the same stage of neuronal differentiation. Regulation of presenilin expression and proteolytic processing might have implications for the pathological as well as the biological function of presenilins during aging in the human brain
— id: 24765, year: 1997, vol: 69, page: 2432, stat: Journal Article,