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Acta Neuropathologica
Published in: Acta Neuropathologica 2/2013

01-02-2013 | Original Paper

Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer’s disease

Authors: Lara Wahlster, Muriel Arimon, Navine Nasser-Ghodsi, Kathryn Leigh Post, Alberto Serrano-Pozo, Kengo Uemura, Oksana Berezovska

Published in: Acta Neuropathologica | Issue 2/2013

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Abstract

Accumulation of amyloid-β (Aβ) and neurofibrillary tangles in the brain, inflammation and synaptic and neuronal loss are some of the major neuropathological hallmarks of Alzheimer’s disease (AD). While genetic mutations in amyloid precursor protein and presenilin-1 and -2 (PS1 and PS2) genes cause early-onset familial AD, the etiology of sporadic AD is not fully understood. Our current study shows that changes in conformation of endogenous wild-type PS1, similar to those found with mutant PS1, occur in sporadic AD brain and during normal aging. Using a mouse model of Alzheimer’s disease (Tg2576) that overexpresses the Swedish mutation of amyloid precursor protein but has normal levels of endogenous wild-type presenilin, we report that the percentage of PS1 in a pathogenic conformation increases with age. Importantly, we found that this PS1 conformational shift is associated with amyloid pathology and precedes amyloid-β deposition in the brain. Furthermore, we found that oxidative stress, a common stress characteristic of aging and AD, causes pathogenic PS1 conformational change in neurons in vitro, which is accompanied by increased Aβ42/40 ratio. The results of this study provide important information about the timeline of pathogenic changes in PS1 conformation during aging and suggest that structural changes in PS1/γ-secretase may represent a molecular mechanism by which oxidative stress triggers amyloid-β accumulation in aging and in sporadic AD brain.
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Metadata
Title
Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer’s disease
Authors
Lara Wahlster
Muriel Arimon
Navine Nasser-Ghodsi
Kathryn Leigh Post
Alberto Serrano-Pozo
Kengo Uemura
Oksana Berezovska
Publication date
01-02-2013
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 2/2013
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-012-1065-6

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