Department of Biology and Center for Developmental Neuroscience, College of Staten Island, The City University of New York, Staten Island, NY, USA.
Department of Neuroscience, The Graduate Center, The City University of New York, New York, NY, USA.
J Alzheimers Dis. 2018;64(s1):S507-S516. doi: 10.3233/JAD-179906.
The microtubule associated protein tau in a hyperphosphorylated form was identified as the building block of the filamentous aggregates found in the neurons of Alzheimer's disease (AD) patients. In the abnormal state, hyperphosphorylated tau from AD brains (AD P-tau) was unable to promote microtubule assembly and more importantly, it could inhibit the normal activity of tau and other MAPs. AD P-tau was able to disrupt preformed microtubules and, by binding to normal tau, turn the latter into an AD P-tau like molecule. AD P-tau toxic behavior was prevalent in the soluble form and it was lost upon dephosphorylation. Mutations on tau associated with disease, e.g., R406W in frontotemporal dementia with Parkinsonism linked to chromosome 17, altered its conformation to make it a better substrate for kinases. Using phospho-mimetics, it was found that the minimum phospho-sites necessary to acquire such a toxic behavior of tau were at 199, 212, 231 and 262, and tau pseudophosphorylated at those sites in combination with R406W was named Pathological Human Tau (PH-Tau). PH-Tau expressed in cells had similar behavior to AD P-tau: disruption of the microtubule system, change in the normal subcellular localization, and gain of toxic function for cells. In animal models expressing PH-Tau, it was found that two putative mechanisms of neurodegeneration exist depending on the concentration of the toxic protein, both involving cognitive decline, due to synaptic dysfunction at lower concentration and neuronal death at higher. Studies investigating the mechanism of tau pathology and its transmission from neuron to neuron are currently ongoing.
过度磷酸化的微管相关蛋白 tau 被鉴定为阿尔茨海默病 (AD) 患者神经元中纤维状聚集物的结构成分。在异常状态下，来自 AD 大脑的过度磷酸化 tau（AD P-tau）无法促进微管组装，更重要的是，它可以抑制 tau 和其他 MAP 的正常活性。AD P-tau 能够破坏预先形成的微管，并通过与正常 tau 结合，将后者转化为 AD P-tau 样分子。AD P-tau 的毒性行为主要以可溶性形式存在，去磷酸化后即丧失。与疾病相关的 tau 突变，例如，与染色体 17 相关的额颞叶痴呆伴帕金森病中的 R406W，改变其构象使其成为激酶更好的底物。使用磷酸模拟物发现，获得 tau 这种毒性行为所需的最小磷酸化位点是 199、212、231 和 262，并且在这些位点被 R406W 磷酸化的 tau 被命名为病理性人 tau（PH-Tau）。在细胞中表达的 PH-Tau 具有与 AD P-tau 相似的行为：破坏微管系统、改变正常亚细胞定位以及获得对细胞的毒性功能。在表达 PH-Tau 的动物模型中，发现存在两种潜在的神经退行性变机制，这两种机制都与毒性蛋白的浓度有关，在较低浓度下涉及突触功能障碍，在较高浓度下涉及神经元死亡，从而导致认知能力下降。目前正在研究 tau 病理学的机制及其在神经元之间的传递。
