Document Detail


Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer's disease.
MedLine Citation:
PMID:  23138650     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Lara Wahlster; Muriel Arimon; Navine Nasser-Ghodsi; Kathryn Leigh Post; Alberto Serrano-Pozo; Kengo Uemura; Oksana Berezovska
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-09
Journal Detail:
Title:  Acta neuropathologica     Volume:  125     ISSN:  1432-0533     ISO Abbreviation:  Acta Neuropathol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-21     Completed Date:  2013-06-25     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  0412041     Medline TA:  Acta Neuropathol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  187-99     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aged, 80 and over
Aging / physiology*
Alzheimer Disease / genetics,  metabolism*
Amyloid beta-Peptides / chemistry,  genetics,  metabolism
Animals
Cells, Cultured
Female
Frontotemporal Lobar Degeneration / genetics
Humans
Immunohistochemistry
Male
Mice
Mice, Transgenic
Microscopy, Fluorescence
Neurons / metabolism
Oxidative Stress
Peptide Fragments / metabolism
Plaque, Amyloid / genetics,  pathology
Presenilin-1 / chemistry*,  genetics
Protein Conformation
Grant Support
ID/Acronym/Agency:
AG15379/AG/NIA NIH HHS; P01 AG015379/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Peptide Fragments; 0/Presenilin-1; 0/amyloid beta-protein (1-40); 0/amyloid beta-protein (1-42)
Comments/Corrections

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