Department of Neurosciences, School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK.
Exp Neurol. 2010 Jun;223(2):401-9. doi: 10.1016/j.expneurol.2009.09.014. Epub 2009 Sep 24.
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.
阿尔茨海默病（AD）的特征是由过度磷酸化的 tau 组成的神经原纤维缠结，以及由错误折叠的淀粉样肽（Abeta(42)）组成的神经突斑块。一般认为，过度磷酸化的 tau 和寡聚 Abeta(42)是导致 AD 早期神经元功能障碍和认知障碍的原因，但它们在致病过程中的相互作用机制尚不清楚。越来越多的证据表明，Abeta(42)病理学位于过度磷酸化的 tau 病理学的上游。同样，人们对每种蛋白质如何影响神经元功能也有了更多的了解。然而，这两种蛋白质中的任何一种对另一种引起的神经元功能障碍的影响并没有得到广泛研究。我们在 AD 的果蝇模型中对此进行了研究，在该模型中我们表达了磷酸化的人 tau（tau(wt)）和寡聚 Abeta(42)。我们发现，tau(wt)的表达通过破坏轴突运输和突触结构导致神经元功能障碍，并导致行为障碍和寿命缩短。Abeta(42)与 tau(wt)的共表达增加了 tau 的磷酸化，并加剧了所有这些由 tau 介导的表型。用 LiCl 处理 tau(wt)/Abeta(42)和果蝇可改善 Abeta(42)的加剧作用，这表明 GSK-3beta 可能参与了 Abeta(42)和 tau(wt)相互作用导致神经元功能障碍的机制。与 Abeta(42)的作用相反，通过与 tau(wt)共表达 dishevelled 模拟 wingless 信号通路，降低了 tau 的磷酸化，并抑制了 tau 介导的表型。因此，可以推测 Abeta(42)在 AD 发病机制中与 tau 相互作用的机制是通过下调内源性 wnt 信号。
