Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment.
Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment.
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DOI：
10.1007/s00401-017-1674-1
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发表时间：
2017-05
影响因子：
12.7
通讯作者：
Götz J
中科院分区：
文献类型：
--
作者：
Hatch RJ;Wei Y;Xia D;Götz J
过度磷酸化的tau蛋白在阿尔茨海默病和额颞叶痴呆等tau病中起关键作用，损害神经元功能并最终导致神经变性。在表达家族性额颞叶痴呆病例中发现的P301L tau突变的转基因小鼠模型中，tau的关键作用得到了研究的支持，该突变在海马体中过度磷酸化的tau的积累导致海马体长期增强减少和空间学习和记忆障碍。然而，过度磷酸化的tau蛋白在降低神经元兴奋性中的作用尚未被探索。在这里，我们在两个互补的P301L tau转基因小鼠模型中发现，过度磷酸化的tau诱导了更多的动作电位启动的去极化阈值，减少了海马CA1神经元的放电，这是通过抑制转基因tau来拯救的。此外，通过诱变和原代海马神经元培养，我们发现这种神经元兴奋性的降低是由于轴突初始段（AIS）以tau磷酸化依赖的方式沿轴突向下迁移造成的。我们还证明了这种效应是微管依赖的。此外，发现药物稳定可以防止由tau过度磷酸化引起的结构和功能缺陷。最后，我们证明了来自tau转基因小鼠的神经元的AIS位于轴突下方，这与兴奋性降低有关。因此，我们提出，由于tau介导的AIS远端再定位导致海马兴奋性降低，有助于在tau病中观察到海马功能障碍。本文的在线版本（doi:10.1007/s00401-017-1674-1）包含补充材料，仅供授权用户使用。
Hyperphosphorylated tau has a critical role in tauopathies such as Alzheimer’s disease and frontotemporal dementia, impairing neuronal function and eventually leading to neurodegeneration. A critical role for tau is supported by studies in transgenic mouse models that express the P301L tau mutation found in cases of familial frontotemporal dementia, with the accumulation of hyperphosphorylated tau in the hippocampus causing reductions in hippocampal long-term potentiation and impairments in spatial learning and memory. However, what has remained unexplored is the role of hyperphosphorylated tau in reducing neuronal excitability. Here, we show in two complementary P301L tau transgenic mouse models that hyperphosphorylated tau induces a more depolarized threshold for action potential initiation and reduces firing in hippocampal CA1 neurons, which was rescued by the suppression of transgenic tau. Furthermore, using mutagenesis and primary hippocampal neuronal cultures, we reveal that this reduction in neuronal excitability results from the relocation of the axon initial segment (AIS) down the axon in a tau phosphorylation-dependent manner. We also demonstrate that this effect is microtubule-dependent. In addition, pharmacological stabilization was found to prevent both the structural and functional deficits caused by tau hyperphosphorylation. Finally, we demonstrate that the AIS of neurons from tau transgenic mice is further down the axon, which correlates with a reduction in excitability. We therefore propose that a reduction in hippocampal excitability due to a tau-mediated distal relocalization of the AIS contributes to the hippocampal dysfunction observed in tauopathies. The online version of this article (doi:10.1007/s00401-017-1674-1) contains supplementary material, which is available to authorized users.