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

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 7

AR-A014418 treatment significantly reduces neuritic plaque formation in AD transgenic mice.

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AR-A014418 treatment significantly reduces neuritic plaque formation in ...
(A and B) APP23/PS45 double transgenic mice at the age of 6 weeks were treated with ARA (5 mg/kg) for 4 weeks, while age-matched control APP23/PS45 mice received vehicle solution. The mice were sacrificed after behavioral tests, and the brains were dissected, fixed, and sectioned. Neuritic plaques were detected using Aβ specific monoclonal antibody 4G8 (Signet). The plaques were visualized by microscopy with ×40 magnification. (A) A representative brain section of the control and (B) AR-A014418 injected APP23/PS45 mice sacrificed immediately after behavioral analysis. Black arrows point to plaques. Bars: 500 μm. The number of neuritic plaques was significantly reduced in AR-A014418 treated mice compared to controls. (C) Quantification of neuritic plaques in APP23/PS45 mice with treatment starting at the age of 6 weeks and sacrificed immediately after behavioral analysis, the number represents mean ± SEM, n = 22 mice total, *P < 0.01 by Student’s t-test. (D and E) Neuritic plaques were further confirmed using thioflavin S fluorescent staining and visualized by microscopy with a ×40 objective. There were less neuritic plaques in AR-A014418 treated mice (E) as compared to age matched control mice (D) sacrificed immediately after AR-A014418 injection. White arrows point to green fluorescent neuritic plaques. Bar: 500 μm. (F and G) Plaque formation in APP23/PS45 mice was further examined using 4G8 antibody staining 3 months after the last injection. (F) A representative brain section of control or (G) AR-A014418 injected APP23/PS45 mice sacrificed 3 months after the last injection. (H) Quantification of neuritic plaques in APP23/PS45 mice 3 months after the last injection. The number represents mean ± SEM, n = 12 mice total, P > 0.05 by Student’s t-test.