Quantitative propagation of assembled human Tau from Alzheimer's disease brain in microfluidic neuronal cultures
Quantitative propagation of assembled human Tau from Alzheimer's disease brain in microfluidic neuronal cultures
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DOI：
10.1074/jbc.ra120.013325
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发表时间：
2020-09-11
影响因子：
4.8
通讯作者：
Bose, Suchira
中科院分区：
文献类型：
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作者：
Katsikoudi, Antigoni;Ficulle, Elena;Bose, Suchira
Tau聚集和过度磷酸化是阿尔茨海默病（AD）的关键神经病理学标志，并且在临床表现期间观察到的Tau的时空扩散表明Tau病理学可能沿着轴突网络扩散并在突触连接的神经元之间传播。在这里，我们已经开发了一种细胞模型，其允许使用微流体装置研究人AD衍生的Tau从神经元到神经元的传播。我们通过使用高内容成像技术和内部开发的交互式计算机程序显示，人AD衍生的Tau种子啮齿动物Tau在微流体培养模型中以可量化的方式跨神经元传播。此外，我们能够将该模型转换为中等通量格式，允许用户在标准96孔板的占地面积中同时处理16个双室装置。此外，我们表明，聚集的小分子抑制剂可以阻断Tau聚集体的跨神经元转移，这表明该系统可用于评估Tau转移的机制并找到治疗干预措施。
Tau aggregation and hyperphosphorylation is a key neuropathological hallmark of Alzheimer's disease (AD), and the temporospatial spread of Tau observed during clinical manifestation suggests that Tau pathology may spread along the axonal network and propagate between synaptically connected neurons. Here, we have developed a cellular model that allows the study of human AD-derived Tau propagation from neuron to neuron using microfluidic devices. We show by using high-content imaging techniques and an in-house developed interactive computer program that human AD-derived Tau seeds rodent Tau that propagates trans-neuronally in a quantifiable manner in a microfluidic culture model. Moreover, we were able to convert this model to a medium-throughput format allowing the user to handle 16 two-chamber devices simultaneously in the footprint of a standard 96-well plate. Furthermore, we show that a small molecule inhibitor of aggregation can block the trans-neuronal transfer of Tau aggregates, suggesting that the system can be used to evaluate mechanisms of Tau transfer and find therapeutic interventions.