2. Academic Validation
  3. BACE2, a conditional β-secretase, contributes to Alzheimer's disease pathogenesis

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.
Zhe Wang 1 2 3,  Qin Xu 2,  Fang Cai 2,  Xi Liu 2,  Yili Wu 4,  Weihong Song 1 2 3
Affiliations

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.
PMID: 30626751 DOI: 10.1172/jci.insight.123431
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.

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