BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis
Zhe Wang, … , Yili Wu, Weihong Song
Zhe Wang, … , Yili Wu, Weihong Song
Published January 10, 2019
Citation Information: JCI Insight. 2019;4(1):e123431. https://doi.org/10.1172/jci.insight.123431.
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Research Article Neuroscience

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

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.

Authors

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

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Figure 5

Clusterin binds APP with intact and wild-type JH intracellularly.

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Clusterin binds APP with intact and wild-type JH intracellularly. (A) Co...
(A) Coimmunoprecipitation (CoIP) of endogenous APP and clusterin from brain homogenate. Anti-GAPDH was used as control IP antibody. (B) Clusterin-FLAG and APPWT without tag were either coexpressed or separately expressed in HEK293 cells. Cells with both clusterin and APP were directly lysed (coexpression), and cells with only clusterin or APP overexpression were lysed and the lysates were combined (pooled lysates). After IP with FLAG-agarose, the precipitated proteins were blotted with C20 antibody for APP and FLAG antibody for clusterin. (C) Schematic diagram showing the position of the JH in different CTFs. (D) C99, C83, and C80 were coexpressed with clusterin-FLAG in HEK293, and the lysates were subjected to anti-FLAG CoIP. C20 antibody was used to detect CTFs in the precipitates. (E) Clusterin-FLAG was coexpressed with wild-type C99 (C99WT), F615P containing C99 (C99F615P), and Flemish mutation containing C99 (C99Fle) in HEK293 cells, and cell lysates were immunoprecipitated using anti-FLAG antibody. Precipitates were Western blotted using C20 for C99 variants and anti-FLAG for clusterin. (F) CoIP of clusterin-FLAG with APP variants in HEK293 cells. IP was by anti-FLAG antibody, and APP detection was by C20 antibody.