机构：[1]The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China.首都医科大学宣武医院国家老年疾病临床医学研究中心[2]Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.[3]Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.[4]Department of Psychiatry, Jining Medical University, Jining, Shandong, China
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.
基金：
CIHR [MOP-142487]; National Science Foundation of China [81870832]; Alzheimer Society of Canada Postdoctoral Fellowship; Chinese Scholarship Council award
第一作者机构：[1]The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China.[2]Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.[3]Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.[*2]Xuanwu Hospital, Capital Medical University, 45 Changchun Road, Beijing 100053, China
共同第一作者：
通讯作者：
通讯机构：[*1]Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.[*2]Xuanwu Hospital, Capital Medical University, 45 Changchun Road, Beijing 100053, China
推荐引用方式(GB/T 7714)：
Zhe Wang ,Qin Xu ,Fang Cai ,et al.BACE2, a conditional beta-secretase, contributes to Alzheimer's disease pathogenesis[J].JCI INSIGHT.2019,4(1):doi:10.1172/jci.insight.123431.
APA：
Zhe Wang,,Qin Xu,,Fang Cai,,Xi Liu,,Yili Wu,&Weihong Song.(2019).BACE2, a conditional beta-secretase, contributes to Alzheimer's disease pathogenesis.JCI INSIGHT,4,(1)
MLA：
Zhe Wang,,et al."BACE2, a conditional beta-secretase, contributes to Alzheimer's disease pathogenesis".JCI INSIGHT 4..1(2019)
医学