BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue Dementia gene BRI2

Shuji Matsuda, Yukiko Matsuda, Luciano D'Adamio

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Alzheimer disease (AD) is characterized by senile plaques, which are mainly composed of β amyloid (Aβ) peptides. Aβ is cleaved off from amyloid precursor protein (APP) with consecutive proteolytic processing: β-secretase, followed by γ-secretase. Here, we show that BRI3, a member of the BRI gene family that includes the familial British and Danish dementia gene BRI2, interacts with APP and serves as an endogenous negative regulator of Aβ production. BRI3 colocalizes with APP along neuritis in differentiated N2a cells; endogenous BRI3-APP complexes are readily detectable in mouse brain extract; reducing endogenous BRI3 levels by RNA interference results in increased Aβ secretion. BRI3 resembles BRI2, because BRI3 overexpression reduces both α and β-APP cleavage. We propose that BRI3 inhibits the various processing of APP by blocking the access of α and β-secretases to APP. However, unlike BRI2, the binding of BRI3 to the β-secretase cleaved APP C-terminal fragment is negligible and BRI3 does not cause the massive accumulation of this APP fragment, suggesting that, unlike BRI2, BRI3 is a poor γ-cleavage inhibitor. Competitive inhibition of APP processing by BRI3 may provide a new approach to AD therapy and prevention.

Original languageEnglish (US)
Pages (from-to)15816-15825
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number23
DOIs
StatePublished - Jun 5 2009

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Amyloid beta-Protein Precursor
Dementia
Genes
Amyloid Precursor Protein Secretases
Processing
Amyloid
Alzheimer Disease
Neuritis
Amyloid Plaques
RNA Interference
Protein C
Brain
RNA
Peptides

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue Dementia gene BRI2. / Matsuda, Shuji; Matsuda, Yukiko; D'Adamio, Luciano.

In: Journal of Biological Chemistry, Vol. 284, No. 23, 05.06.2009, p. 15816-15825.

Research output: Contribution to journalArticle

Matsuda, Shuji ; Matsuda, Yukiko ; D'Adamio, Luciano. / BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue Dementia gene BRI2. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 23. pp. 15816-15825.
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