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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
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
PMID: 16990547
ISSN: 1095-9203
CID: 81091

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
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
PMCID:1559665
PMID: 16906128
ISSN: 1469-221x
CID: 95394

Targeting the role of the endosome in the pathophysiology of Alzheimer's disease: a strategy for treatment

Tate, Barbara A; Mathews, Paul M
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
PMID: 16807486
ISSN: 1539-6150
CID: 95395

Endosome function and pathology in Alzheimer's disease [Meeting Abstract]

Cataldo, AM; Mathews, PM; Peterhoff, CM; Boyer-Boiteau, A; Jiang, Y; Nixon, RA
ISI:000235982900184
ISSN: 0022-3042
CID: 62904

Dysregulation of brain APP in the Ts65Dn Down syndrome mouse [Meeting Abstract]

Choi, JHK; Diaz, NS; Mazzella, MJ; Peterson, JN; Cataldo, AM; Ginsberg, SD; Levy, E; Nixon, RA; Mathews, PM
ORIGINAL:0008404
ISSN: 1552-5260
CID: 463402

APP expression modulated AD-related endosomal trafficking abnormalities in Down syndrome fibroblasts [Meeting Abstract]

Jiang, Y; Mullaney, KA; Che, S; Schmidt, SD; Mathews, PM; Cataldo, AM; Ginsberg, SD; Nixon, RA
ORIGINAL:0008403
ISSN: 1552-5260
CID: 463392

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
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
PMCID:2171227
PMID: 16203860
ISSN: 0021-9525
CID: 60255

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
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
PMCID:1149500
PMID: 15951428
ISSN: 0027-8424
CID: 95396

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
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
PMID: 15322109
ISSN: 0021-9258
CID: 95398

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
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
PMID: 15311281
ISSN: 1097-6256
CID: 95399