Axonal microtubules are essential for transport of materials to the synapse. Compromised microtubules and synaptic loss have been demonstrated in AD (Alzheimer's disease), which is believed to contribute to cognitive dysfunction before neuronal death in the early stages of the disease. The mechanism by which hyperphosphorylated tau, the building block of neurofibrillary tangles, one of the pathological hallmarks of AD, disrupts neuronal and synaptic function is unclear. There is a theory that hyperphosphorylated tau does not bind effectively to microtubules and is no longer able to function in stabilizing them, thus axonal transport can no longer proceed efficiently. This leads to synaptic dysfunction. We have tested this theory in a Drosophila model of tauopathies in which we expressed human tau (h-tau). Using this model, we have tested all aspects of this hypothesis and have demonstrated that axonal transport does become compromised in the presence of hyperphosphorylated h-tau and this leads to synaptic and behavioural defects. We are currently investigating the mechanism by which hyperphosphorylated h-tau mediates this effect and are preliminary data indicate that this entails phospho-tau-mediated effects that are predicted by the tau–microtubule hypothesis, as well as novel effects. These deleterious effects of h-tau occur in the absence of tau filaments and before neuronal death. This sequence of pathogenic events may constitute the mechanism by which abnormal tau disrupts neuronal and synaptic function and contributes to cognitive impairment before neuronal death in the early stages of tauopathies such as AD.
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April 2010
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Conference Article|
March 22 2010
Disruption of neuronal function by soluble hyperphosphorylated tau in a Drosophila model of tauopathy
Catherine M. Cowan;
Catherine M. Cowan
1School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, U.K.
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Francis Chee;
Francis Chee
1School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, U.K.
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David Shepherd;
David Shepherd
1School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, U.K.
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Amritpal Mudher
Amritpal Mudher
1
1School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, U.K.
1To whom correspondence should be addressed (email C.M.Cowan@soton.ac.uk).
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Biochem Soc Trans (2010) 38 (2): 564–570.
Article history
Received:
September 24 2009
Citation
Catherine M. Cowan, Francis Chee, David Shepherd, Amritpal Mudher; Disruption of neuronal function by soluble hyperphosphorylated tau in a Drosophila model of tauopathy. Biochem Soc Trans 1 April 2010; 38 (2): 564–570. doi: https://doi.org/10.1042/BST0380564
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