Aβ exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease

Alzheimer's disease (AD) is characterised by neurofibrillary tangles composed of hyper-phosphorylated tau, and neuritic plaques composed of misfolded amyloid peptide (Aβ42). It is generally believed that the hyper-phosphorylated tau and oligomeric Aβ42 are responsible for the neuronal dysfunction and cognitive impairments that underlie the early stages of AD, but the mechanism by which they interact in the pathogenic process is not clear. Mounting evidence suggests that Aβ42 pathology lies upstream of hyper-phosphorylated tau pathology. Similarly much is being learnt about how each protein affects neuronal function. However, the impact that either pathological protein has on neuronal dysfunction caused by the other is not extensively studied. We have investigated this in a Drosophila model of AD in which we express both phosphorylated human tau (tauwt) and oligomeric Aβ42. We find that expression of tauwt causes neuronal dysfunction by disrupting axonal transport and synaptic structure, and that this leads to behavioural impairments and reduced lifespan. Co-expression of Aβ42 with tauwt increases tau phosphorylation and exacerbates all these tau-mediated phenotypes. Treatment of tauwt/Aβ42 and flies with LiCl ameliorates the exacerbating effect of Aβ42, suggesting that GSK-3β may be involved in the mechanism by which Aβ42 and tauwt interact to cause neuronal dysfunction. Conversely to the effect of Aβ42, mimicking the wingless signalling pathway by co-expression of dishevelled with tauwt reduces tau phosphorylation and suppresses the tau-mediated phenotypes. It is therefore possible to speculate that the mechanism by which Aβ42 interacts with tau in the pathogenesis of AD is by down-regulating endogenous wnt signalling.