The DOI matches its Crossref record; 34 of the 35 references it cites were found in a registry or an index.
GSK-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila
Abstract
The tauopathies are a group of disorders characterised by aggregation of the microtubule-associated protein tau and include Alzheimer's disease (AD) and the fronto-temporal dementias (FTD). We have used Drosophila to analyse how tau abnormalities cause neurodegeneration. By selectively co-expressing wild-type human tau (0N3R isoform) and a GFP vesicle marker in motorneurons, we examined the consequences of tau overexpression on axonal transport in vivo. The results show that overexpression of tau disrupts axonal transport causing vesicle aggregation and this is associated with loss of locomotor function. All these effects occur without neuron death. Co-expression of constitutively active glycogen-synthase kinase-3beta (GSK-3beta) enhances and two GSK-3beta inhibitors, lithium and AR-A014418, reverse both the axon transport and locomotor phenotypes, suggesting that the pathological effects of tau are phosphorylation dependent. These data show that tau abnormalities significantly disrupt neuronal function, in a phosphorylation-dependent manner, before the classical pathological hallmarks are evident and also suggest that the inhibition of GSK-3beta might have potential therapeutic benefits in tauopathies.
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“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 [94]
In the citing paper
“Drosophila models expressing human tau recapitulate key features of human tauopathies, including progressive neurodegeneration and phosphorylation at AD-related sites via conserved kinases [41, 44, 53, 59–63].”
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The GSK3 hypothesis of Alzheimer’s disease
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Metadata
- Authors
- Mudher, A., Shepherd, D., Newman, T. A., Mildren, P., Jukes, J. P., Squire, A., Mears, A., Berg, S., MacKay, D., Asuni, A. A., Bhat, R., & Lovestone, S.
- Affiliations
- King's College London (GB)
- University of Southampton (GB)
- AstraZeneca (Sweden) (SE)
- Corresponding author
- Lovestone, S
- Venue
- Molecular Psychiatry
- Published
- 2004-03-02
- Volume
- 9
- Issue
- 5
- Pages
- 522-530
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2020815630
- Cited by
- 265
- References
- 35
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 6 · 2023: 5 · 2022: 9 · 2021: 7 · 2020: 11 · 2019: 9 · 2018: 9 · 2017: 11 · 2016: 11 · 2015: 9 · 2014: 18 · 2013: 14 · 2012: 22
- FWCI
- 9.66
- Type
- journal article
- Language
- en
- Update notices
- erratum (2004-07-26)
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Keywords
- tauopathy, glycogen synthase kinase-3β, GSK-3β inhibition, tau phosphorylation, axonal transport, vesicle aggregation, locomotor dysfunction, motor neurons, lithium, AR-A014418, Alzheimer's disease, frontotemporal dementia, neurodegeneration, Drosophila model
- MeSH terms
- Animals, Axons, Axonal Transport, Drosophila melanogaster, Enzyme Inhibitors, Humans, Larva, Locomotion, Phosphorylation, Protein Processing, Post-Translational, Recombinant Fusion Proteins, Thiazoles, Urea, tau Proteins, Lithium Chloride, Tauopathies, Drosophila Proteins, Glycogen Synthase Kinase 3
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