P1-025: Neurotoxicity due to overexpression of Drosophila tau is comparable to that seen with human tau

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Neurofibrillary tangles containing the microtubule–associated protein tau, together with extracellular amyloid plaques comprise the two characteristic neuropathological features of Alzheimer's disease. Tau found in these tangles has been shown to be abnormal in a number of aspects including phosphorylation status and filament formation. Similar abnormalities in tau are also associated with a group of disorders collectively known as tauopathies. To model these disorders, human tau has been overexpressed in neuronal populations in Drosophila melanogaster resulting in neuronal degeneration, diminished locomotor activity, disrupted axonal transport and impaired synaptic function. These effects are seen prior to neuronal death and in the absence of tangle formation. It is not yet known how the effects of overexpression of human tau in Drosophila compare to overexpression of Drosophila tau. Though the Drosophila tau protein shares a large degree of homology with human tau, it differs in that it contains five putative microtubule–binding regions (compared to the maximum of four in human tau) and lacks the N–terminal repeats which are a feature of human tau. The UAS–Gal4 targeted gene expression system was used to overexpress Drosophila tau in motorneurons in third instar larvae in order to compare the effects of overexpression of Drosophila tau with that of human tau. The locomotor abilities and axonal transport characteristics of these larvae were assessed as previously described (Mudher et al. 2004) and compared with those of larvae in which human 3RT had been overexpressed. Overexpression of Drosophila tau led to a similar decrease in locomotor activity to that seen with overexpression of human 3RT. The effects of overexpression of Drosophila tau on axonal transport are currently under investigation. These results show that overexpression of Drosophila tau leads to neurotoxicity that is comparable to that seen with overexpression of human tau. This indicates that it is overexpression of tau per se that is detrimental to neuronal function and that neuronal degeneration is not a feature of the specific overexpression of human tau in these models.