Mudher A, Shepherd D, Newman T A, Mildren P, Jukes J P, Squire A, Mears A, Drummond J A, Berg S, MacKay D, Asuni A A, Bhat R, Lovestone S
Department of Neuroscience and Old Age Psychiatry, Institute of Psychiatry, Kings College London, De Crespigny Park, London, UK.
Mol Psychiatry. 2004 May;9(5):522-30. doi: 10.1038/sj.mp.4001483.
The tauopathies are a group of disorders characterised by aggregation of the microtubule-associated protein tau and include Alzheimer's disease (AD) and the fronto-temporal dementias (FTD). We have used Drosophila to analyse how tau abnormalities cause neurodegeneration. By selectively co-expressing wild-type human tau (0N3R isoform) and a GFP vesicle marker in motorneurons, we examined the consequences of tau overexpression on axonal transport in vivo. The results show that overexpression of tau disrupts axonal transport causing vesicle aggregation and this is associated with loss of locomotor function. All these effects occur without neuron death. Co-expression of constitutively active glycogen-synthase kinase-3beta (GSK-3beta) enhances and two GSK-3beta inhibitors, lithium and AR-A014418, reverse both the axon transport and locomotor phenotypes, suggesting that the pathological effects of tau are phosphorylation dependent. These data show that tau abnormalities significantly disrupt neuronal function, in a phosphorylation-dependent manner, before the classical pathological hallmarks are evident and also suggest that the inhibition of GSK-3beta might have potential therapeutic benefits in tauopathies.
tau蛋白病是一组以微管相关蛋白tau聚集为特征的疾病，包括阿尔茨海默病（AD）和额颞叶痴呆（FTD）。我们利用果蝇来分析tau异常如何导致神经退行性变。通过在运动神经元中选择性地共表达野生型人tau（0N3R亚型）和绿色荧光蛋白囊泡标记物，我们研究了tau过表达对体内轴突运输的影响。结果表明，tau过表达会破坏轴突运输，导致囊泡聚集，这与运动功能丧失有关。所有这些效应都在神经元未死亡的情况下发生。组成型活性糖原合酶激酶-3β（GSK-3β）的共表达会增强这些效应，而两种GSK-3β抑制剂锂和AR-A014418则可逆转轴突运输和运动表型，这表明tau的病理效应是磷酸化依赖性的。这些数据表明，在经典病理特征出现之前，tau异常就以磷酸化依赖性方式显著破坏神经元功能，并且还表明抑制GSK-3β可能对tau蛋白病具有潜在的治疗益处。
