Cited by 446Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Ly, Philip T.T., Wu, Yili, Zou, Haiyan, Wang, Ruitao, Zhou, Weihui, Kinoshita, Ayae, Zhang, Mingming, Yang, Yi, Cai, Fang, Woodgett, James, Song, Weihong·2013·Journal of Clinical Investigation

DOI 10.1172/jci64516PMC PMC3533290

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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.

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See all 446

Authors: Ly, P. T. T., Wu, Y., Zou, H., Wang, R., Zhou, W., Kinoshita, A., Zhang, M., Yang, Y., Cai, F., Woodgett, J., & Song, W.
Affiliations: University of British Columbia (CA)
Lunenfeld-Tanenbaum Research Institute (CA)
Kyoto University (JP)
Corresponding author: Song, Weihong
ORCID: Ly, Philip T.T.
Wu, Yili
Zou, Haiyan
Wang, Ruitao
Zhou, Weihui
Kinoshita, Ayae
Zhang, Mingming
Cai, Fang
Woodgett, James
Song, Weihong
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2012-12-03
Volume: 123
Issue: 1
Pages: 224-235
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci64516
PMC: PMC3533290
OpenAlex: W2168597028
Cited by: 442
References: 105
Citations by year: 2026: 32 · 2025: 50 · 2024: 43 · 2023: 46 · 2022: 34 · 2021: 36 · 2020: 29 · 2019: 30 · 2018: 20 · 2017: 27 · 2016: 21 · 2015: 21 · 2014: 34 · 2013: 19
FWCI: 15.86
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Michael Smith Health Research BC
National Natural Science Foundation of China
Canadian Institutes of Health Research (117948_1, 97825_1)
Natural Sciences and Engineering Research Council of Canada
Japan Society for the Promotion of Science
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Alzheimer's disease, GSK3β, BACE1, amyloid-beta, APP processing, beta-secretase, gamma-secretase, NF-κB signaling, neuritic plaques, memory impairment, GSK3 inhibition, transcriptional regulation
MeSH terms: Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Animals, Disease Models, Animal, Enzyme Activation, Humans, Transcription, Genetic, Signal Transduction, Gene Expression Regulation, Enzymologic, Aspartic Acid Endopeptidases, NF-kappa B, Amyloid beta-Protein Precursor, Mice, Knockout, Glycogen Synthase Kinase 3, Mice, Amyloid Precursor Protein Secretases, HEK293 Cells, Plaque, Amyloid

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

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