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

ABSTRACT: Deposition of amyloid-? protein (A?) to form neuritic plaques is the characteristic neuropathology of Alzheimer's disease (AD). A? is generated from amyloid precursor protein (APP) by ?- and ?-secretase cleavages. BACE1 is the ?-secretase and its inhibition induces severe side effects, whereas its homolog BACE2 normally suppresses A? by cleaving APP/A? at the ?-site (Phe20) within the A? domain. Here, we report that BACE2 also processes APP at the ? site, and the juxtamembrane helix (JH) of APP inhibits its ?-secretase activity, enabling BACE2 to cleave nascent APP and aggravate AD symptoms. JH-disrupting mutations and clusterin binding to JH triggered BACE2-mediated ?-cleavage. Both BACE2 and clusterin were elevated in aged mouse brains, and enhanced ?-cleavage during aging. Therefore, BACE2 contributes to AD pathogenesis as a conditional ?-secretase and could be a preventive and therapeutic target for AD without the side effects of BACE1 inhibition.

SUBMITTER: Wang Z

PROVIDER: S-EPMC6485359 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Wang Zhe Z Xu Qin Q Cai Fang F Liu Xi X Wu Yili Y Song Weihong W

JCI insight 20190110 1

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 ...[more]

PMID: 30626751

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