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

被引：82

作者：

Matsuda, Shuji ^{[1
]}

Giliberto, Luca ^{[1
]}

Matsuda, Yukiko ^{[1
]}

McGowan, Eileen M. ^{[2
]}

D'Adamio, Luciano ^{[1
,3
]}

机构：

[1] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA

[2] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA

[3] Univ Naples Federico II, Dipartimento Biochim & Biotecnol Med, CEINGE Biotecnol Avanzate, I-80145 Naples, Italy

来源：

JOURNAL OF NEUROSCIENCE | 2008年 / 28卷 / 35期

基金：

美国国家卫生研究院;

关键词：

amyloid-beta; Alzheimer's disease; BRI2; familial dementia; synaptic plasticity; mice;

D O I：

10.1523/JNEUROSCI.2094-08.2008

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Genetic alterations of amyloid beta-peptide (A beta) production caused by mutations in the A beta 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 A beta production. BRI2 restrict docking of gamma-secretase to APP and access of alpha- and beta-secretases to their cleavage APP sequences. Alterations of BRI2 by gene targeting or transgenic expression regulate A beta 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.

引用

页码：8668 / 8676

页数：9

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