Role of presenilin in γ-secretase cleavage of amyloid precursor protein

Research output: Contribution to journalReview article

22 Scopus citations

Abstract

Cerebral accumulation of the amyloid β-protein (Aβ) is an early and invariant event in the pathogenesis of Alzheimer's disease (AD). Mutations in the presenilin (PS) 1 and 2 genes that increase production of the highly amyloidogenic Aβ42 are the most common cause of familial AD. Deletion of PS1 in mice reduces Aβ generation, indicating that PS1 mediates the last step in the generation of Aβ from β-amyloid precursor protein (APP) by the unidentified γ-secretase. Mutating either of two conserved transmembrane aspartates in PS1 significantly reduced Aβ production and increased the APP C-terminal fragments that are γ-secretase substrates. These results indicate that PS1 is either a unique diaspartyl cofactor for γ-secretase or is itself γ-secretase. Furthermore, studies on the γ-secretase-like proteolytic processing of Notch and Ire1 suggest a common mechanism for the involvement of PS1 in intramembrane proteolysis of membrane proteins. (C) 2000 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)453-460
Number of pages8
JournalExperimental Gerontology
Volume35
Issue number4
DOIs
StatePublished - Jul 1 2000

Keywords

  • Alzheimer's disease
  • Amyloid β-protein
  • Presenilin

ASJC Scopus subject areas

  • Aging
  • Medicine(all)

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