BACE2, a conditional β-secretase, contributes to Alzheimer's disease pathogenesis
BACE2, a conditional β-secretase, contributes to Alzheimer's disease pathogenesis
复制标题
BACE2 是一种条件性 β 分泌酶，与阿尔茨海默病的发病机制有关
DOI：
10.1172/jci.insight.123431
复制
发表时间：
2019-01-10
期刊：
影响因子：
8
通讯作者：
Song, Weihong
中科院分区：
文献类型：
--
作者：
Wang, Zhe;Xu, Qin;Song, Weihong
淀粉样β蛋白(Aβ)沉积形成神经性斑块是阿尔茨海默病(AD)的典型神经病理特征。β是由淀粉样前体蛋白(APP)通过β-和伽马分泌酶裂解而产生的。BACE1是β-分泌酶，它的抑制会导致严重的副作用，而它的同系物BACE2通常通过在Aβ结构域中的theta位点(Phe(20))裂解APP/Aβ来抑制Aβ。在这里，我们报告BACE2也在Beta位点处理APP，APP的膜旁螺旋(JH)抑制其β-分泌酶活性，使BACE2能够裂解新生的APP并加重AD症状。JH-破坏突变和聚集素与JH的结合触发了BACE2介导的β-切割。BACE2和Clusterin在衰老小鼠脑中均升高，并在衰老过程中增强了β-裂解。因此，BACE2作为一种条件性β-分泌酶参与了AD的发病过程，可以作为AD的预防和治疗靶点，而不存在BACE1抑制的副作用。
Deposition of amyloid-beta protein (A beta) to form neuritic plaques is the characteristic neuropathology of Alzheimer's disease (AD). A beta is generated from amyloid precursor protein (APP) by beta- and gamma-secretase cleavages. BACE1 is the beta-secretase and its inhibition induces severe side effects, whereas its homolog BACE2 normally suppresses A beta by cleaving APP/A beta at the theta-site (Phe(20)) within the A beta domain. Here, we report that BACE2 also processes APP at the beta site, and the juxtamembrane helix (JH) of APP inhibits its beta-secretase activity, enabling BACE2 to cleave nascent APP and aggravate AD symptoms. JH-disrupting mutations and clusterin binding to JH triggered BACE2-mediated beta-cleavage. Both BACE2 and clusterin were elevated in aged mouse brains, and enhanced beta-cleavage during aging. Therefore, BACE2 contributes to AD pathogenesis as a conditional beta-secretase and could be a preventive and therapeutic target for AD without the side effects of BACE1 inhibition.