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 4

BACE2 suppression reduces C99 and Aβ accumulation in the brains of APP Arctic mutation–knockin mice.

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BACE2 suppression reduces C99 and Aβ accumulation in the brains of APP A...
(A) Primary neurons from E18 APPSwedish-Arctic-Iberian/Swedish-Arctic-Iberian–knockin mice (3KI) or APPSwedish-Iberian/Swedish-Iberian–knockin mice (2KI) were transduced with adeno-associated virus-9 (AAV9) carrying scrambled shRNA (scr) or shRNA against mouse BACE2 (sh). Cells were analyzed by Western blot for CTFs (C-terminal fragments of APP), APP, BACE2, and BACE1.NA-CTF, nonamyloidogenic C-terminal fragments of APP. (B) Viruses containing scrambled shRNA or BACE2 shRNA were intraventricularly injected into the brains of neonatal 3KI mice (all littermates, n = 5 for each). Mice were sacrificed at 11 postnatal weeks. Half brains were Western blotted for the indicated proteins. C99 on the same membrane was also blotted with C99-specific antibody 82E1, and merged with C20 blots. Nonamyloidogenic CTFs (NA-CTFs) include C89, C83, and C80. CTRL, control scrambled shRNA. (C) The other brain halves were analyzed by Aβ1–42 ELISA. ELISA readout for Aβ1–40 was no higher than background noise (n = 5). (D) AAV9 carrying scrambled shRNA or shBACE2 were intraventricularly injected into the brains of neonatal 3KI (all littermates) or 2KI (all littermates) mice. Successful injection was indicated by fast dye (blue). Mice were sacrificed 2 weeks after virus injection, and brain homogenates in RIPA buffer were Western blotted for the indicated proteins. C99 levels were expressed as percentages of C99 in scramble shRNA–injected 3KI mice. n = 4 for 3KI Ctrl, 3KI shBACE2, and 2KI shBACE2, and n = 3 for 2KI control. (E) Y-maze test for 6-month-old 3KI mice with or without BACE2 suppression. n = 8 for wild-type mice (WT), 4 for 3KI, and 8 for 3KI with suppressed BACE2 expression (KD). *P < 0.05; **P < 0.01; ***P < 0.001 by unpaired t test. ns, non-significant. All bars represent mean ± SEM.