Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau
Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau
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DOI：
10.1007/s00401-007-0207-8
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发表时间：
2007-05-01
影响因子：
12.7
通讯作者：
Iqbal, Khalid
中科院分区：
文献类型：
--
作者：
Li, Bin;Chohan, Muhammad Omar;Iqbal, Khalid
过度磷酸化的tau蛋白长期以来被认为是破坏正常神经元微管动力学并导致阿尔茨海默病神经元变性的关键分子。在这里，我们提供了一个直接的证据，过度磷酸化的tau蛋白诱导的微管网络的破坏。使用Nocodozole处理和洗涤剂提取的细胞，我们创造了一个神经元的环境，在小鼠胚胎成纤维细胞，3T3细胞，取代其细胞质与成年大鼠脑细胞质。通过在这些细胞中重建神经元微管网络，我们能够在真实的时间内跟踪过度磷酸化tau蛋白对微管动力学的影响。重组人脑tau蛋白促进微管的组装和成束，而从阿尔茨海默病脑胞质溶胶中分离的异常过度磷酸化的tau蛋白（AD P-tau）通过隔离正常脑tau蛋白和MAP 2抑制组装并破坏预先形成的微管网络。用蛋白磷酸酶-2A处理提取的细胞可逆转微管网络的这种破坏。这项研究，第一次，提供了直接的机制洞察到阿尔茨海默病中看到的轴突和树突神经变性的分子基础。
Hyperphosphorylated tau has long been proposed as the key molecule disrupting normal neuronal microtubule dynamics and leading to neurofibrillary degeneration in Alzheimer disease. Here we provide a direct evidence of hyperphosphorylated tau-induced disruption of microtubule network. Using Nocodozole-treated and detergent-extracted cells, we created a neuronal environment in mouse embryonic fibroblasts, 3T3 cells, by replacing their cytoplasm with adult rat brain cytosol. By recreating neuronal microtubule network in these cells, we were able to follow the effects of hyperphosphorylated tau on microtubule dynamics in real time. Whereas recombinant human brain tau promoted assembly and bundling of microtubules, abnormally hyperphosphorylated tau isolated from Alzheimer disease brain cytosol (AD P-tau) inhibited the assembly and disrupted preformed microtubule network by sequestering normal brain tau and MAP2. This breakdown of the microtubule network was reversed by treatment of the extracted cells with protein phosphatase-2A. This study, for the first time, provides direct mechanistic insights into the molecular basis of both axonal and dendritic neurodegeneration seen in Alzheimer disease.