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

作者：Folwell James; Cowan Catherine M; Ubhi Kiren K; Shiabh Hassan; Newman Tracey A; Shepherd David; Mudher Amritpal^*

来源：Experimental Neurology, 2010, 223(2): 401-409.

DOI：10.1016/j.expneurol.2009.09.014

• Animal model
• Axonal transport
• Drosophila model
• GSK-3 beta
• Synaptic dysfunction
• wnt/wingless signalling

Alzheimer's disease (AD) is characterised by neurofibrillary tangles composed of hyper-phosphorylated tau, and neuritic plaques composed of misfolded amyloid peptide (A beta(42)). It is generally believed that the hyper-phosphorylated tau and oligomeric A beta(42) 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 A beta(42) 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 (tau(wt)) and oligomeric A beta(42). We find that expression of tau(wt) causes neuronal dysfunction by disrupting axonal transport and synaptic structure, and that this leads to behavioural impairments and reduced lifespan. Co-expression of A beta(42) with tau(wt) increases tau phosphorylation and exacerbates all these tau-mediated phenotypes. Treatment of tau(wt)/A beta(42) and flies with LiCl ameliorates the exacerbating effect of A beta(42), suggesting that GSK-3 beta may be involved in the mechanism by which A beta(42) and tau(wt) interact to cause neuronal dysfunction. Conversely to the effect of A beta(42), mimicking the wingless signalling pathway by co-expression of dishevelled with tau(wt) reduces tau phosphorylation and suppresses the tau-mediated phenotypes. It is therefore possible to speculate that the mechanism by which A beta(42) interacts with tau in the pathogenesis of AD is by down-regulating endogenous wnt signalling.

• 出版日期2010-6