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.
View: Text | PDF
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

×

Figure 1

Perturbation of the JH domain by proline causes BACE2-mediated β-cleavages.

Options: View larger image (or click on image) Download as PowerPoint
Perturbation of the JH domain by proline causes BACE2-mediated β-cleavag...
(A) Schematic diagram showing the cleavage sites and mutation sites in APP. JH, juxtamembrane helix; TM, transmembrane domain. (B) APP695 wild type (APPWT) and APP F615P mutant (numbering as in APP695 form; APPF615P) were coexpressed in HEK293 cells with Myc-His–tagged BACE1 or BACE2, and cell lysates were blotted for CTFs, APP, and BACEs. Both BACE1 and BACE2 were detected using 9E10 anti-Myc antibody. Ratios of C99 to C89 were plotted. Bars represent mean ± SEM (n = 3). (C) Proline-scanning mutagenesis of the APP JH domain. All residues from V614 to D619 of APP695 were individually replaced by proline, and the mutants were coexpressed in HEK293 with BACE2. Cell lysates were immunoblotted for CTFs, APP, and BACE2. (D) APPWT and the non–membrane-binding APPG625W were coexpressed with BACE2. CTFs were enriched by IP with C20 antibody, and Western blotted with both C20 polyclonal and the C99-specific 82E1 antibody.