Increased level of active GSK‐3β in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration
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The somatodendritic accumulation of hyperphosphorylated tau proteins is an early event preceding the appearance of neurofibrillary tangles (NFT) in Alzheimer’s disease (AD) and might be necessary for their formation. Glycogen synthase kinase‐3β (GSK‐3β) is a physiological kinase for tau that generates many tau phosphorylation sites identified in NFT and in other tau‐positive inclusions. We have studied the cellular distribution and the expression of the active form of GSK‐3β (GSK‐3 pTyr216) in AD patients, in argyrophilic grain disease and in diffuse Lewy body disease. By Western blotting analysis, a significant increase in the level of GSK‐3 (pTyr216) was observed in the frontal cortex of AD patients. A population of neurones showed a somatodendritic accumulation of GSK‐3 (pTyr216) but not of the inactive form of GSK‐3β (GSK‐3 pSer9). Most of these GSK‐3 (pTyr216)‐positive cells were positive for six different phosphotau epitopes known to be generated by GSK‐3β. By using a quadruple labelling method using GSK‐3 (pTyr216) and phosphotau immunolabelling combined with Gallyas and DAPI staining, we examined neurones containing a somatodendritic GSK‐3 (pTyr216) immunoreactivity at different stages of neurodegeneration. A majority of neurones at the pretangle stage without Gallyas‐positive inclusions were GSK‐3 (pTyr216) positive and this GSK‐3 (pTyr216) immunoreactivity remained in most cells containing Gallyas and phosphotau‐positive inclusions excepted in extracellular NFT. A GSK‐3 (pTyr216) immunoreactivity was present in argyrophilic grains but not in cortical Lewy bodies. These results directly suggest that the activity of GSK‐3β is increased in AD and that somatodendritic accumulation and activation of GSK‐3β is an early event preceding and accompanying the formation of NFT and of other tau‐positive inclusions.
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GSK3β expression is increased in AD.
“To examine whether increased expression of GSK3β in AD [33] is connected to SGK1”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [33]
The Results section reports that total GSK-3β levels were not significantly different between AD cases and controls; only the active pTyr216 form increased significantly. The Discussion explicitly says total GSK-3β levels were not increased in AD, contrary to the unqualified claim of increased GSK-3β expression. (LLM, conf=0.90)
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“Again, SGK1 knockdown or inhibition in AD neurons reduced HDAC6 while SGK1 over-expression in control neurons increased HDAC6.”
- Authors
- Leroy, K., Yilmaz, Z., & Brion, J. ‐.
- Affiliations
- Université Libre de Bruxelles (BE)
- Venue
- Neuropathology and Applied Neurobiology
- Publisher
- Wiley
- Published
- 2007-01-12
- Volume
- 33
- Issue
- 1
- Pages
- 43-55
- ISSN
- 0305-1846 (ISSN-L)
- 1365-2990
- OpenAlex
- W1989036097
- Cited by
- 404
- References
- 6
- Citations by year
- 2026: 10 · 2025: 36 · 2024: 30 · 2023: 37 · 2022: 22 · 2021: 37 · 2020: 31 · 2019: 17 · 2018: 13 · 2017: 15 · 2016: 13 · 2015: 20 · 2014: 22 · 2013: 15 · 2012: 19
- FWCI
- 10.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropathology and Applied Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
- 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, glycogen synthase kinase-3β, tau hyperphosphorylation, neurofibrillary tangles, argyrophilic grains, Lewy bodies, frontal cortex, neurodegeneration
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Aged, Aged, 80 and over, Alzheimer Disease, Epitopes, Cell Nucleus, Dendrites, Female, Fluorescent Dyes, Humans, Immunohistochemistry, Indoles, Male, Middle Aged, Neurons, Phosphorylation, Immunoblotting, Neurofibrillary Tangles, tau Proteins, Prefrontal Cortex, Lewy Body Disease, Glycogen Synthase Kinase 3
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