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 6

The binding of clusterin to the JH facilitates BACE2-mediated β-cleavages.

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The binding of clusterin to the JH facilitates BACE2-mediated β-cleavage...
(A) APPWT (no tag) and BACE2 (Myc-His tagged) were expressed in HEK293 in the presence or absence (vector) of coexpressed clusterin (Myc-His tagged). CTFs were enriched by immunoprecipitation (IP) with C20 antibody, and blotted with 82E1 antibody specific for C99. (B) Clusterin or ApoEs whose binding motif in Aβ resides in the JH region as well were overexpressed in 4EB2 cells, a HEK293 cell stably expressing human APP Swedish mutant (APPSwe) and BACE2. Total CTFs were blotted with C20 antibody and C99 was also blotted with 82E1. C99s were quantified (using C20 polyclonal) and expressed as the ratio to C99 in vector-expressing cells (n = 4 replicates). ***P < 0.001 (1-way ANOVA, Tukey’s post hoc test). (C) APPSwe or APPF615P were coexpressed with either pcDNA4 or clusterin-FLAG in 4B25 cells, a HEK293 cell line stably expressing Myc-tagged human BACE2. C99 levels were expressed as the ratio to C99 in pcDNA4-APP–expressing cells (n = 3 replicates). **P < 0.01 (paired t tests). (D) Nascent APP (APPER) and BACE2 were coexpressed with pcDNA4 (vector, clusterin “–”) or clusterin (clusterin “+”) in HEK293 cells. C80 bands were quantified and plotted as the ratio to C80 in vector-expressing (clusterin “–”) cells (n = 3 replicates). **P < 0.01 (paired t tests). (E) Clusterin was coexpressed in PC12 cells with APPSwe or the APP Swedish-F615P double mutant (APPSwe-F615P). Forty-eight hours after transfection, cell lysates were blotted for the indicated proteins and conditioned media were analyzed by Aβ1–42 ELISA. The amounts of Aβ1–42 were expressed as the ratio to Aβ1–42 from cells with pcDNA4 transfection (Vec) (n = 3 replicates). **P < 0.01 (paired t tests). All bars represent mean ± SEM.