Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo
Open accessAbstract
Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo , transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically.
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Inhibition or genetic reduction of GSK-3β ameliorates tau-related deficits.
“many investigators have shown that either inhibition or genetic reduction of GSK-3β ameliorates tau-related deficits (94–99).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [95]
The Results and Discussion (page numbers unavailable) report that lithium reduced GSK-3β activity and that treatment with GSK-3 inhibitors was associated with less aggregated tau and degeneration in mice. The paper does not report genetic reduction of GSK-3β, so it supports the inhibition part of the claim but not the genetic-reduction part. (LLM, conf=0.87)
Experimental — accuracy not yet measuredGSK-3β inhibition reduces tau hyperphosphorylation and neurofibrillary tangle formation in tau-overexpressing transgenic mice.
“Inhibition of GSK-3β may have dual benefits given that GSK-3β inhibition reduces tau hyperphosphorylation and NFT formation in tau-overexpressing transgenic mice (Noble et al., 2005; Engel et al., 2006; Leroy et al., 2010) and produces anticonvulsant effects against pentylenetetrazol-induced seizures in zebrafish larvae (Aourz et al., 2019).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Noble et al., 2005
The Results report reduced tau phosphorylation and aggregated, insoluble tau after GSK-3 inhibition in mice overexpressing mutant human tau. But the Discussion says MC1 staining did not significantly decrease and that it is unknown whether treatment reduced mature tangle load. Thus, reduced neurofibrillary tangle formation is not established by this paper. (LLM, conf=0.90)
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- Authors
- Noble, W., Planel, E., Zehr, C., Olm, V., Meyerson, J., Suleman, F., Gaynor, K., Wang, L., LaFrancois, J., Feinstein, B., Burns, M., Krishnamurthy, P., Wen, Y., Bhat, R., Lewis, J., Dickson, D., & Duff, K.
- Affiliations
- Mayo Clinic (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-05-02
- Volume
- 102
- Issue
- 19
- Pages
- 6990-6995
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2087745495
- Cited by
- 709
- References
- 2
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 30 · 2023: 22 · 2022: 24 · 2021: 19 · 2020: 29 · 2019: 25 · 2018: 21 · 2017: 31 · 2016: 26 · 2015: 27 · 2014: 40 · 2013: 44 · 2012: 39
- FWCI
- 29.69
- Type
- journal article
- Language
- en
- Open access
- green
- dx.doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Alzheimer's Association
- National Institute on Aging (AG172116)
- National Institute of Neurological Disorders and Stroke (P01NS040256, NS 40256, P50NS040256)
- 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 › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Keywords
- glycogen synthase kinase-3, lithium chloride, tauopathy, tau hyperphosphorylation, neurofibrillary tangles, Alzheimer's disease, axonal degeneration, kinase inhibitors, transgenic mice, tau aggregation
- MeSH terms
- Animals, Epitopes, Enzyme Inhibitors, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Lithium, Mice, Transgenic, Neurons, Phosphorylation, Immunoblotting, tau Proteins, Lithium Chloride, Disease Progression, Neurodegenerative Diseases, Tauopathies, Glycogen Synthase Kinase 3, Immunoprecipitation, Mice
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