Aβ exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease
Aβ exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease
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DOI：
10.1016/j.expneurol.2009.09.014
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发表时间：
2010-06-01
影响因子：
5.3
通讯作者：
Mudher, Amritpal
中科院分区：
文献类型：
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作者：
Folwell, James;Cowan, Catherine M.;Mudher, Amritpal
阿尔茨海默病（AD）的特征是由过度磷酸化的tau蛋白组成的神经原纤维缠结和由错误折叠的淀粉样肽组成的神经斑块（A β(42)）。人们普遍认为，过度磷酸化的tau蛋白和寡聚物A β(42)是阿尔茨海默病早期的神经元功能障碍和认知障碍的原因，但它们在致病过程中相互作用的机制尚不清楚。越来越多的证据表明A β(42)病理位于超磷酸化tau病理的上游。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，其中一种病理蛋白对另一种病理蛋白引起的神经元功能障碍的影响尚未得到广泛研究。我们在AD的果蝇模型中研究了这一点，我们表达了磷酸化的人tau（tau(wt)）和寡聚物a β(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，从而导致行为障碍和寿命缩短。A β(42)与tau（wt）的共表达增加了tau磷酸化并加剧了所有这些tau介导的表型。用LiCl治疗tau(wt)/A β(42)和果蝇可以改善A β(42)的恶化作用，这表明GSK-3 β可能参与了A β(42)和tau（wt）相互作用导致神经元功能障碍的机制。与A β的作用相反（42），通过与tau共表达disheveled （wt）来模拟无翼信号通路可减少tau磷酸化并抑制tau介导的表型。因此，可以推测A β(42)在AD发病过程中与tau相互作用的机制是通过下调内源性wnt信号传导。爱思唯尔公司2009年版权所有版权所有。
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. Crown Copyright (C) 2009 Published by Elsevier Inc. All rights reserved.