β位点淀粉样前体蛋白裂解酶2（BACE2）作为一种条件性β分泌酶，参与阿尔茨海默病的发病机制。
BACE2, a conditional β-secretase, contributes to Alzheimer's disease pathogenesis.
作者信息
Wang Zhe, Xu Qin, Cai Fang, Liu Xi, Wu Yili, Song Weihong
机构信息
The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China.
Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
出版信息
JCI Insight. 2019 Jan 10;4(1):e123431. doi: 10.1172/jci.insight.123431.
Deposition of amyloid-β protein (Aβ) to form neuritic plaques is the characteristic neuropathology of Alzheimer's disease (AD). Aβ is generated from amyloid precursor protein (APP) by β- and γ-secretase cleavages. BACE1 is the β-secretase and its inhibition induces severe side effects, whereas its homolog BACE2 normally suppresses Aβ by cleaving APP/Aβ at the θ-site (Phe20) within the Aβ domain. Here, we report that BACE2 also processes APP at the β site, and the juxtamembrane helix (JH) of APP inhibits its β-secretase activity, enabling BACE2 to cleave nascent APP and aggravate AD symptoms. JH-disrupting mutations and clusterin binding to JH triggered BACE2-mediated β-cleavage. Both BACE2 and clusterin were elevated in aged mouse brains, and enhanced β-cleavage during aging. Therefore, BACE2 contributes to AD pathogenesis as a conditional β-secretase and could be a preventive and therapeutic target for AD without the side effects of BACE1 inhibition.
淀粉样β蛋白（Aβ）沉积形成神经炎性斑块是阿尔茨海默病（AD）的典型神经病理学特征。Aβ由淀粉样前体蛋白（APP）经β和γ分泌酶切割产生。β位点淀粉样前体蛋白裂解酶1（BACE1）是β分泌酶，抑制它会引发严重的副作用，而其同源物BACE2通常通过在Aβ结构域内的θ位点（苯丙氨酸20）切割APP/Aβ来抑制Aβ。在此，我们报告BACE2也在β位点加工APP，且APP的近膜螺旋（JH）抑制其β分泌酶活性，使得BACE2能够切割新生的APP并加重AD症状。JH破坏突变以及簇集素与JH结合会引发BACE2介导的β切割。在老年小鼠大脑中，BACE2和簇集素均升高，且在衰老过程中增强了β切割。因此，BACE2作为一种条件性β分泌酶参与AD发病机制，并且可能成为AD的预防和治疗靶点，而不会产生抑制BACE1的副作用。
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