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

Cowan, Catherine M., Page, Anton, Bossing, Torsten, Shepherd, David and Mudher, Amritpal (2010) Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo Acta Neuropathologica, 120, (5), pp. 523-655.

Record type: Article

Abstract

It has been hypothesised that tau protein, when hyper-phosphorylated as in AD, does not bind effectively to microtubules and is no longer able to stabilize 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 two-fold: firstly, as predicted by the tau-microtubule hypothesis, the highly phosphorylated tau exhibits significantly reduced binding to microtubules, and secondly, 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 cytoskeletal integrity. Notably, all these phospho-tau mediated phenotypes occur in the absence of tau filament/ neurofibrillary tangle formation or neuronal death, and may thus constitute the mechanism by which hyper-phosphorylated tau disrupts neuronal function and contributes to cognitive impairment prior to neuronal death in the early stages of tauopathies.

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More information

Published date: May 2010
Keywords: alzheimer's disease, tauopathy, axonal transport, lithium, neurofibrillary tangles
Organisations: Biological Sciences

Identifiers

Local EPrints ID: 155753
URI: http://eprints.soton.ac.uk/id/eprint/155753
ISSN: 0001-6322
PURE UUID: 0d1acbde-de5a-499c-b830-4cc16dd64380
ORCID for David Shepherd: ORCID iD orcid.org/0000-0002-4561-8184

Catalogue record

Date deposited: 28 May 2010 12:00
Last modified: 30 Sep 2017 11:54

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Contributors

Author: Catherine M. Cowan
Author: Anton Page
Author: Torsten Bossing
Author: David Shepherd ORCID iD
Author: Amritpal Mudher

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