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

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 +3 more·2013·Journal of Clinical Investigation

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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  • GSK3β is known to be involved in the regulation of APP metabolism, Tau phosphorylation and synaptic functions, making it a potential link between PLCγ2 and the phenotypes associated with its downregulation.

    “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.”

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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
Venue
Journal of Clinical Investigation
Published
2012-12-03
Volume
123
Issue
1
Pages
224-235
ISSN
0021-9738 (ISSN-L)
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
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
  • Health Sciences › Medicine › Physiology › 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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