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

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

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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Crossref · 10.1007/s00401-010-0716-8

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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).”

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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
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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