Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo
Abstract
It has been hypothesised that tau protein, when hyper-phosphorylated as in Alzheimer's disease (AD), does not bind effectively to microtubules and is no longer able to stabilise them; thus microtubules break down, and axonal transport can no longer proceed efficiently in affected brain regions in AD and related tauopathies (tau-microtubule hypothesis). We have used Drosophila models of tauopathy to test all components of this hypothesis in vivo. We have previously shown that upon expression of human 0N3R tau in Drosophila motor neurons it becomes highly phosphorylated, resulting in disruptions to both axonal transport and synaptic function which culminate in behavioural phenotypes. We now show that the mechanism by which the human tau mediates these effects is twofold: first, as predicted by the tau-microtubule hypothesis, the highly phosphorylated tau exhibits significantly reduced binding to microtubules; and second, it participates in a pathogenic interaction with the endogenous normal Drosophila tau and sequesters it away from microtubules. This causes disruption of the microtubular cytoskeleton as evidenced by a reduction in the numbers of intact correctly-aligned microtubules and the appearance of microtubules that are not correctly oriented within the axon. These deleterious effects of human tau are phosphorylation dependent because treatment with LiCl to suppress tau phosphorylation increases microtubule binding of both human and Drosophila tau and restores cytoskelet…
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The uncoupling of Aβ42 effects on LTP by MAPT-N296H occurs at the level of tau phosphorylation.
“This suggests that the uncoupling of Aβ42 effects on LTP by MAPT-N296H occurs at the level of tau phosphorylation which could feed directly into the formation of small soluble tau oligomers (Cowan et al., 2010).”
From Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice (2017) · cites this paper as Cowan et al., 2010
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Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies
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Rescue from tau-induced neuronal dysfunction produces insoluble tau oligomers
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Reducing PDK1/Akt Activity: An Effective Therapeutic Target in the Treatment of Alzheimer’s Disease
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Post-translational modifications in neurodegeneration
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Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration
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Differences in Synaptic Dysfunction Between rTg4510 and APP/PS1 Mouse Models of Alzheimer’s Disease
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The Fruit Fly, Drosophila melanogaster: Modeling of Human Diseases (Part II)
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The Power and Richness of Modelling Tauopathies in Drosophila
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Studying tauopathies in Drosophila: A fruitful model
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How do neurons age? A focused review on the aging of the microtubular cytoskeleton
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Modelling Tauopathies in Drosophila : Insights from the Fruit Fly
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Self-citationAn evaluation of Drosophila as a model system for studying tauopathies such as Alzheimer’s disease
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Self-citationInsights from Drosophila models of Alzheimer's disease
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Self-citationCurcumin as a Holistic Treatment for Tau Pathology
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Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice
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Alzheimer’s disease: an axonal injury disease?
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Disruption of Microtubule Integrity Initiates Mitosis during CNS Repair
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Self-citationThe Drosophila model system to study tau action
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Tau Protein: Function and Pathology
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- Authors
- Cowan, C. M., Bossing, T., Page, A., Shepherd, D., & Mudher, A.
- Affiliations
- University of Southampton (GB)
- Southampton General Hospital (GB)
- Corresponding author
- Mudher, Amritpal
- Venue
- Acta Neuropathologica
- Published
- 2010-07-09
- Volume
- 120
- Issue
- 5
- Pages
- 593-604
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2085782370
- Cited by
- 156
- References
- 51
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 19 · 2023: 9 · 2022: 5 · 2021: 7 · 2020: 9 · 2019: 7 · 2018: 3 · 2017: 16 · 2016: 4 · 2015: 9 · 2014: 8 · 2013: 11 · 2012: 10
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- tau hyperphosphorylation, tauopathy, Alzheimer's disease, microtubule binding, axonal transport, lithium chloride, microtubule cytoskeleton, synaptic function, cognitive impairment
- MeSH terms
- Animals, Drosophila, Humans, Immunohistochemistry, Microtubules, Motor Neurons, Phosphorylation, Blotting, Western, tau Proteins, Tauopathies, Microscopy, Electron, Transmission, Immunoprecipitation
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