BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis
Zhe Wang, Qin Xu, Fang Cai, Xi Liu, Yili Wu, Weihong Song
Zhe Wang, Qin Xu, Fang Cai, Xi Liu, Yili Wu, Weihong Song
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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 2

AD-associated APP mutations perturbed the JH domain and induced β-cleavage by BACE2.

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AD-associated APP mutations perturbed the JH domain and induced β-cleava...
(A) APP variants were coexpressed in HEK293 cells with BACE2 or inactive BACE2 mutant (D110A). Cell lysates were blotted for CTFs, APP, and BACE2. CTF markers expressed in HEK293 cells were loaded to indicate the mobility of CTFs. CTFs were blotted with rabbit polyclonal C20 antibody against the last 20 residues of APP, and the same membrane was also blotted with C99/Aβ(1–x)–specific mouse monoclonal antibody 82E1. The color panel is the merged images of C20 and 82E1 on the same gel. For clear visualization of C99 and C89 from APP mutants, Western blot membranes were exposed for a longer time. For the comparison of C83/C80, membranes were exposed for a shorter time. (B) APP variants were coexpressed with BACE1 or BACE2 in HEK293 cells, and CTFs were simultaneously blotted with the rabbit polyclonal C20 antibody and the mouse monoclonal 82E1 antibody. Images of C20 (red) and 82E1 (green) bands were merged in the bottom panel. Ratios of 82E1 signals to C20 signals were plotted, and comparison was by paired t tests. (C) APP wild type, Flemish, and Arctic mutants were coexpressed with either BACE1-Myc or BACE2-Myc in HEK293 cells. Cell lysates were blotted for APP, CTFs, and BACEs. (D) APPWT, Flemish, Arctic, and APPF615P mutants were coexpressed with BACE2-Myc-His in PC12 cells. Cell lysates were immunoblotted for indicated proteins and the conditioned media were measured for Aβ1–40. All bars represent mean ± SEM (n = 3). ***P < 0.001 (paired t tests). WT, APP wild type; APPFle and Fle, APP Flemish mutant; APPArc and Arc, APP Arctic mutant.