RESUMEN
Alzheimer's disease (AD) is characterised by neurofibrillary tangles composed of hyper-phosphorylated tau, and neuritic plaques composed of misfolded amyloid peptide (Abeta(42)). It is generally believed that the hyper-phosphorylated tau and oligomeric Abeta(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 Abeta(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 Abeta(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 Abeta(42) with tau(wt) increases tau phosphorylation and exacerbates all these tau-mediated phenotypes. Treatment of tau(wt)/Abeta(42) and flies with LiCl ameliorates the exacerbating effect of Abeta(42), suggesting that GSK-3beta may be involved in the mechanism by which Abeta(42) and tau(wt) interact to cause neuronal dysfunction. Conversely to the effect of Abeta(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 Abeta(42) interacts with tau in the pathogenesis of AD is by down-regulating endogenous wnt signalling.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/genética , Transporte Axonal/fisiología , Drosophila/fisiología , Fragmentos de Péptidos/genética , Proteínas tau/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Regulación hacia Abajo/fisiología , Drosophila/genética , Proteínas de Drosophila/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Locomoción/fisiología , Longevidad/fisiología , Unión Neuromuscular/patología , Unión Neuromuscular/fisiología , Neuronas/patología , Neuronas/fisiología , Fragmentos de Péptidos/metabolismo , Fenotipo , Fosforilación/fisiología , Transducción de Señal/fisiología , Sinapsis/patología , Sinapsis/fisiología , Proteína Wnt1/metabolismo , Proteínas tau/metabolismoRESUMEN
Hyperphosphorylation and aggregation of tau into tangles is a feature of disorders such as Alzheimer's disease and other Tauopathies. To model these disorders in Drosophila melanogaster, human tau has been over-expressed and a variety of phenotypes have been observed including neurotoxicity, disrupted neuronal and synaptic function and locomotor impairments. Neuronal dysfunction has been seen prior to neuronal death and in the absence of tangle formation. The Drosophila tau protein shares a large degree of homology with human tau but differs in the crucial microtubule binding domains. Although like human tau Drosophila tau can induce neurotoxicity, little is known about its ability to disrupt neuronal function. In this study we demonstrate that like human tau, over-expression of Drosophila tau results in disrupted axonal transport, altered neuromuscular junction morphology and locomotor impairments. This indicates that like human tau, over-expression of Drosophila tau compromises neuronal function despite significant differences in microtubule binding regions.