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Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes
Philip T.T. Ly, … , James Woodgett, Weihong Song
Philip T.T. Ly, … , James Woodgett, Weihong Song
Published December 3, 2012
Citation Information: J Clin Invest. 2013;123(1):224-235. https://doi.org/10.1172/JCI64516.
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Research Article Neuroscience

Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes

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Abstract

Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer’s disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β- and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating γ-secretase activity, thereby facilitating Aβ production. There are two highly conserved isoforms of GSK3: GSK3α and GSK3β. We now report that specific inhibition of GSK3β, but not GSK3α, reduced BACE1-mediated cleavage of APP and Aβ production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3β was dependent on NF-κB signaling. Inhibition of GSK3 signaling markedly reduced Aβ deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3β and that inhibition of GSK3 signaling can reduce Aβ neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the β-isoform of GSK3 may be a safe and effective approach for treating AD.

Authors

Philip T.T. Ly, Yili Wu, Haiyan Zou, Ruitao Wang, Weihui Zhou, Ayae Kinoshita, Mingming Zhang, Yi Yang, Fang Cai, James Woodgett, Weihong Song

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Figure 1

Specific inhibition of GSK3 reduces BACE1 cleavage of APP.

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Specific inhibition of GSK3 reduces BACE1 cleavage of APP.
(A) Swedish m...
(A) Swedish mutant APP stable cell line 20E2 was cultured and treated with ARA for 24 hours, and cell lysates subjected to Western blot analysis. Full-length APP and the APP CTFs were detected with C20 antibody. β-Catenin was detected by anti–β-catenin antibody. β-Actin was detected by anti-actin antibody AC-15 as the internal control. (B) Quantification of APP C99 generation in 20E2 cells. ARA treatment significantly increased β-catenin levels in a dose-dependent manner, while APP C99 production decreased with increasing ARA dosage. n = 6; *P < 0.05 and **P < 0.01, ANOVA. Aβ ELISA detection of Aβ40 (C) and Aβ42 (D) in conditioned medium from 20E2 cells treated with ARA for 24 hours. ARA treatment reduced Aβ levels in the conditioned medium in a dose-dependent manner. The values are expressed as mean ± SEM. n = 4; *P < 0.05, ANOVA. (E) γ-Secretase activity in 20E2 cells was inhibited by the pharmacological inhibitor L685,458 (GSI). Co-treatment with specific GSK3 inhibitors ARA and G2 reduced C99. Con, control. (F) Quantification of C99 levels. n = 6; *P < 0.05, ANOVA.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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