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Disruption of neuronal function by soluble hyperphosphorylated tau in a Drosophila model of tauopathy

By Catherine M. Cowan, Francis Chee, David Shepherd and Amritpal Mudher


Axonal microtubules are essential for transport of materials to the synapse. Compromised microtubules<br/>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. <br/><br/>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. <br/><br/>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<br/>have tested all aspects of this hypothesis and have demonstrated that axonal transport does become<br/>compromised in the presence of hyperphosphorylated h-tau and this leads to synaptic and behavioural defects. <br/><br/>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 affects that are predicted by the tau–microtubule hypothesis, as well as novel effects. <br/><br/>These deleterious effects of h-tau occur in the<br/>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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