BRI2 inhibits amyloid β-peptide precursor protein processing by interfering with the docking of secretases to the substrate

Shuji Matsuda, Luca Giliberto, Yukiko Matsuda, Eileen M. McGowan, Luciano D'Adamio

Research output: Contribution to journalArticle

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Abstract

Genetic alterations of amyloid β-peptide (Aβ) production caused by mutations in the Aβ precursor protein (APP) cause familial Alzheimer's disease (AD). Mutations in BRI2, a gene of undefined function, are linked to familial British and Danish dementias, which are pathologically and clinically similar to Alzheimer's disease. We report that BRI2 is a physiological suppressor of Aβ production. BRI2 restrict docking of γ-secretase to APP and access of α- and β-secretases to their cleavage APP sequences. Alterations of BRI2 by gene targeting or transgenic expression regulate Aβ levels and AD pathology in mouse models of AD. Competitive inhibition of APP processing by BRI2 may provide a new approach to AD therapy and prevention.

Original languageEnglish (US)
Pages (from-to)8668-8676
Number of pages9
JournalJournal of Neuroscience
Volume28
Issue number35
DOIs
StatePublished - Aug 27 2008

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Keywords

  • Alzheimer's disease
  • Amyloid-β
  • BRI2
  • Familial dementia
  • Mice
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

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