BACE2, a conditional β-secretase, contributes to Alzheimer's disease pathogenesis

作者：Wang, Zhe^*; Xu, Qin; Cai, Fang; Liu, Xi; Wu, Yili; Song, Weihong^*

来源：JCI Insight, 2019, 4(1): e123431.

DOI：10.1172/jci.insight.123431

• AMYLOID-PRECURSOR PROTEIN
• CLEAVING ENZYME 2
• APOLIPOPROTEIN-J
• CLUSTERIN/APOLIPOPROTEIN-J
• ASPARTYL PROTEASE
• CLEAVAGE SITE
• MOUSE MODEL
• CLUSTERIN
• APP
• EXPRESSION

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.

• 出版日期2019-1-10
• 单位济宁医学院; 首都医科大学