The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
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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“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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Braak, H., Thal, D. R., Ghebremedhin, E., & Del Tredici, K. (2011) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318232a379 · Cited by 2,194
The pathological process underlying Alzheimer’s disease in individuals under thirty
Braak, H., & Del Tredici, K. (2011) · Acta Neuropathologica · doi:10.1007/s00401-010-0789-4 · Cited by 812
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Braak, H., & Del Tredici, K. (2015) · Brain · doi:10.1093/brain/awv236 · Cited by 540
Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation
Huat, T. J., Camats‐Perna, J., Newcombe, E. A., Valmas, N., Kitazawa, M., & Medeiros, R. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.01.018 · Cited by 501
Tau Protein Modifications and Interactions: Their Role in Function and Dysfunction
Mietelska‐Porowska, A., Wasik, U., Goras, M., Filipek, A., & Niewiadomska, G. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15034671 · Cited by 431
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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