Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: Generation of paired helical filament epitopes and neuronal localisation of the kinase
Abstract
Glycogen synthase kinase-3 (GSK-3) reduced the mobility of human tau on SDS-PAGE, prevented binding of the monoclonal antibody (mAb), Tau.1, and induced binding of the mAb 8D8. Recombinant tau phosphorylated by GSK-3 aligned on SDS-PAGE with the abnormally phosphorylated tau (PHF-tau) associated with the paired helical filaments in Alzheimer's disease brain. Phosphorylated serine396 (numbering of the largest human brain tau isoform) was identified as a binding site on tau for mAb 8D8. The localisation of GSK-3 within granular structures in pyramidal cells indicates that GSK-3 alpha and GSK-3 beta may have a role in the production of PHF-tau in Alzheimer's disease.
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Prior studies of tau phosphorylation by these kinases were carried out in vitro without exception.
“However, without exception, these studies have been carried out in vitro.”
From Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells (1995) · cites this paper as [7]
The results extend in vitro findings to an in vivo model system and indicate that GSK3β may be involved in tau phosphorylation in vivo.
“They extend results obtained in vitro [7,12,14] to an in vivo model system, and indicate that GSK3fl may be involved in the phosphorylation of tau in vivo.”
From Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells (1995) · cites this paper as [7]
MAP kinase, GSK3, and neuronal cdc2-like kinase (cdk5) have been shown to phosphorylate tau in vitro at sites that are phosphorylated in PHFs.
“Mitogen-activated protein kinase, glycogen synthase kinase-3 (GSK3) and neuronal cdc2-1ike kinase have been shown to phosphorylate tau protein in vitro at a number of sites that are phosphorylated in PHFs.”
From Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells (1995) · cites this paper as [7]
GSK3β probably was directly responsible for the increased immunoreactivities and mobility shifts observed, because in vitro studies demonstrated that tau can be directly phosphorylated by GSK3β at many of the same sites.
“However, since in vitro studies [7,12,14] have demonstrated that tau can be directly phosphorylated by GSK3fl at many of the sites we observed in transfected cells, GSK3fl probably was directly responsible for the increased immunoreactivities and mobility shifts observed here.”
From Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells (1995) · cites this paper as [7]
par-1 and shaggy are known tau kinases.
“Two modifiers identified in an unbiased manner from these screens, par-1 and shaggy, are known tau kinases (24,25,90–92)”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [24]
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- Authors
- Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J.-P., & Anderton, B. H.
- Affiliations
- Ludwig Cancer Research (GB)
- Université Libre de Bruxelles (BE)
- Corresponding author
- Hanger, Diane P.
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 1992-11
- Volume
- 147
- Issue
- 1
- Pages
- 58-62
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W2073128231
- Cited by
- 737
- References
- 2
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 19 · 2023: 19 · 2022: 21 · 2021: 24 · 2020: 23 · 2019: 20 · 2018: 18 · 2017: 19 · 2016: 20 · 2015: 20 · 2014: 17 · 2013: 38 · 2012: 23
- FWCI
- 14.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- Wellcome Trust
- 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 › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- glycogen synthase kinase-3, tau phosphorylation, Alzheimer's disease, paired helical filaments, GSK3β, pyramidal neurons, granular structure
- MeSH terms
- Alzheimer Disease, Brain Chemistry, Electrophoresis, Polyacrylamide Gel, Hippocampus, Humans, Intermediate Filaments, Neurons, Phosphorylation, Protein Kinases, Recombinant Proteins, Blotting, Western, tau Proteins, Calcium-Calmodulin-Dependent Protein Kinases, Glycogen Synthase Kinases
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