Acta Neuropathologica

, Volume 125, Issue 2, pp 187–199 | Cite as

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

  • Lara Wahlster
  • Muriel Arimon
  • Navine Nasser-Ghodsi
  • Kathryn Leigh Post
  • Alberto Serrano-Pozo
  • Kengo Uemura
  • Oksana Berezovska
Original Paper

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.

Keywords

Alzheimer’s disease Aging Presenilin-1 Amyloid beta Oxidative stress 

Supplementary material

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Supplementary material 1 (DOC 82 kb)
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Supplementary material 2 (TIFF 2169 kb)
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Supplementary material 3 (TIFF 13649 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Lara Wahlster
    • 1
    • 2
  • Muriel Arimon
    • 1
  • Navine Nasser-Ghodsi
    • 1
  • Kathryn Leigh Post
    • 1
  • Alberto Serrano-Pozo
    • 1
  • Kengo Uemura
    • 1
  • Oksana Berezovska
    • 1
  1. 1.Department of Neurology, MassGeneral Institute for Neurodegenerative Disease (MIND)Massachusetts General Hospital, Harvard Medical SchoolCharlestownUSA
  2. 2.Institute of Physiology and Pathophysiology, University of HeidelbergHeidelbergGermany

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