Cited by 156Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsMicrotubule and mitosis dynamics

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Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo

Cowan, Catherine M., Bossing, Torsten, Page, Anton, Shepherd, David, Mudher, Amritpal·2010·Acta Neuropathologica

DOI 10.1007/s00401-010-0716-8

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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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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
ORCID: Bossing, Torsten
Shepherd, David
Mudher, Amritpal
Venue: Acta Neuropathologica
Publisher: Springer Science and Business Media LLC
Published: 2010-07-09
Volume: 120
Issue: 5
Pages: 593-604
ISSN: 0001-6322 (ISSN-L)
1432-0533
DOI: 10.1007/s00401-010-0716-8
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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Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo

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