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Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes
Open accessAbstract
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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“GSK3β is already known to be involved in the regulation of APP metabolism, Tau phosphorylation and synaptic functions41–43, making it a potential link between PLCγ2 and the different phenotypes associated with its downregulation.”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [43]
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Metadata
- 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
- Venue
- Journal of Clinical Investigation
- Published
- 2012-12-03
- Volume
- 123
- Issue
- 1
- Pages
- 224-235
- ISSN
- 0021-9738 (ISSN-L)
- 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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