Distribution of Active Glycogen Synthase Kinase 3β (GSK-3β) in Brains Staged for Alzheimer Disease Neurofibrillary Changes
Abstract
Accumulation of paired helical filaments (PHFs) in neurofibrillary tangles, neuropil threads, and dystrophic neurites is one of the major neuropathological hallmarks of Alzheimer disease (AD). The principal protein subunit of PHFs is the abnormally hyperphosphorylated tau. Glycogen synthase kinase 3beta (GSK-3beta) is one of the candidate kinases involved in PHF-tau formation. To play a role in PHF-tau formation, it would be expected that GSK-3beta is active in tangle bearing neurons. In the present study, we investigated the regional and intracellular distributions of active and inactive forms of GSK-3beta in brains staged for neurofibrillary changes. We found that neurons with tangle-like inclusions positive for active, but not inactive, GSK-3beta appear initially in the Pre-alpha layer of the entorhinal cortex and extend to other brain regions, coincident with the sequence of the development of neurofibrillary changes. Active, but not inactive, GSK-3beta was found to initially accumulate in the cytoplasm of pretangle neurons. These data provide direct in situ evidence that is consistent with the involvement of GSK-3beta in PHF-tau formation.
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More than 20 serine/threonine kinases are reported to phosphorylate tau in vitro, including GSK-3β, Cdk5, MARK1-4, ERK, p38α MAPK, and JNK.
“In fact, there are currently more than 20 serine/threonine kinases reported to phosphorylate tau in vitro: glycogen synthase kinase 3 beta (GSK-3β), cyclin-dependent kinase 5 (Cdk5), microtubule affinity regulating kinase 1–4 (MARK1–MAPK4), extracellular signal-related kinase (ERK), p38 mitogen-associated protein kinase alpha (p38α MAPK), and c-Jun N-terminal kinase (JNK) are the best examples [19”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [19]
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- Authors
- Pei, J.-J., Braak, E., Braak, H., Grundke-Iqbal, I., Iqbal, K., Winblad, B., & Cowburn, R. F.
- Affiliations
- Karolinska Institutet (SE)
- Goethe University Frankfurt (DE)
- Corresponding author
- Pei, Jin-Jing
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-09
- Volume
- 58
- Issue
- 9
- Pages
- 1010-1019
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W2031864556
- Cited by
- 459
- References
- 0
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 10 · 2023: 14 · 2022: 10 · 2021: 9 · 2020: 11 · 2019: 13 · 2018: 14 · 2017: 9 · 2016: 13 · 2015: 18 · 2014: 27 · 2013: 28 · 2012: 15
- FWCI
- 6.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag008076-09, 5r01ns018105-17)
- National Institute on Aging (AG 08076)
- National Institute of Neurological Disorders and Stroke (NS 18105)
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- glycogen synthase kinase-3β, Alzheimer's disease, neurofibrillary tangles, paired helical filaments, tau hyperphosphorylation, entorhinal cortex, neuropathological staging
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Immunohistochemistry, Isoenzymes, Male, Middle Aged, Neurofibrils, Neurons, Phosphorylation, Tissue Distribution, tau Proteins, Calcium-Calmodulin-Dependent Protein Kinases, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3
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