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

Zhe Wang; Qin Xu; Fang Cai; Xi Liu; Yili Wu; Weihong Song

doi:10.1172/jci.insight.123431

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

JCI Insight. 2019 Jan 10;4(1):e123431. doi: 10.1172/jci.insight.123431.

Authors

Zhe Wang^{1

2

3}, Qin Xu², Fang Cai², Xi Liu², Yili Wu⁴, Weihong Song^{1

2

3}

Affiliations

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.
⁴ Department of Psychiatry, Jining Medical University, Jining, Shandong, China.

Abstract

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.

Keywords: Alzheimer’s disease; Neuroscience.