The familial dementia BRI2 gene binds the alzheimer gene amyloid-β precursor protein and inhibits amyloid-β production

Shuji Matsuda, Luca Giliberto, Yukiko Matsuda, Peter Davies, Eileen McGowan, Fiona Pickford, Jorge Ghiso, Blas Frangione, Luciano D'Adamio

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Alzheimer disease (AD), the most common senile dementia, is characterized by amyloid plaques, vascular amyloid, neurofibrillary tangles, and progressive neurodegeneration. Amyloid is mainly composed by amyloid-β (Aβ) peptides, which are derive from processing of the β-amyloid precursor protein (APP), better named amyloid-β precursor protein (AβPP), by secretases. The AβPP intracellular domain (AID), which is released together with Aβ, has signaling function, since it modulates apoptosis and transcription. Despite its biological and pathological importance, the mechanisms regulating AβPP processing are poorly understood. As cleavage of other γ-secretase substrates is regulated by membrane bound proteins, we have postulated the existence of integral membrane proteins that bind AβPP and regulate its processing. Here, we show that BRI2, a type II membrane protein, interacts with AβPP. Interestingly, 17 amino acids corresponding to the NH2-terminal portion of Aβ are necessary for this interaction. Moreover, BRI2 expression regulates AβPP processing resulting in reduced Aβ and AID levels. Altogether, these findings characterize the BRI2-AβPP interaction as a regulatory mechanism of AβPP processing that inhibits Aβ production. Notably, BRI2 mutations cause familial British (FBD) and Danish dementias (FDD) that are clinically and pathologically similar to AD. Finding that BRI2 pathogenic mutations alter the regulatory function of BRI2 on AβPP processing would define dysregulation of AβPP cleavage as a pathogenic mechanism common to AD, FDD, and FBD.

Original languageEnglish (US)
Pages (from-to)28912-28916
Number of pages5
JournalJournal of Biological Chemistry
Issue number32
StatePublished - Aug 12 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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