BRI2 inhibits amyloid β-peptide precursor protein processing by interfering with the docking of secretases to the substrate
BRI2 inhibits amyloid β-peptide precursor protein processing by interfering with the docking of secretases to the substrate
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DOI：
10.1523/jneurosci.2094-08.2008
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发表时间：
2008-08-27
影响因子：
5.3
通讯作者：
D'Adamio, Luciano
中科院分区：
文献类型：
--
作者：
Matsuda, Shuji;Giliberto, Luca;D'Adamio, Luciano
淀粉样β-肽（A β）产生的遗传改变由A β前体蛋白（APP）中的突变引起，从而引起家族性阿尔茨海默病（AD）。BRI 2是一种功能不明的基因，其突变与家族性英国和丹麦痴呆症有关，这些痴呆症在病理和临床上与阿尔茨海默病相似。我们报道BRI 2是A β产生的生理抑制剂。BRI 2限制γ-分泌酶与APP的对接以及α-和β-分泌酶接近其裂解APP序列。通过基因靶向或转基因表达改变BRI 2调节AD小鼠模型中的A β水平和AD病理学。BRI 2对APP加工的竞争性抑制可能为AD的治疗和预防提供新的途径。
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.