Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago 7800020, Chile.
Indian Scientific Education and Technology Foundation, Lucknow 226002, India.
Int J Mol Sci. 2022 Apr 10;23(8):4192. doi: 10.3390/ijms23084192.
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease characterized by progressive cognitive impairment, apathy, and neuropsychiatric disorders. Two main pathological hallmarks have been described: neurofibrillary tangles, consisting of tau oligomers (hyperphosphorylated tau) and Aβ plaques. The influence of protein kinases and phosphatases on the hyperphosphorylation of tau is already known. Hyperphosphorylated tau undergoes conformational changes that promote its self-assembly. However, the process involving these mechanisms is yet to be elucidated. In vitro recombinant tau can be aggregated by the action of polyanions, such as heparin, arachidonic acid, and more recently, the action of polyphosphates. However, how that process occurs in vivo is yet to be understood. In this review, searching the most accurate and updated literature on the matter, we focus on the precise molecular events linking tau modifications, its misfolding and the initiation of its pathological self-assembly. Among these, we can identify challenges regarding tau phosphorylation, the link between tau heteroarylations and the onset of its self-assembly, as well as the possible metabolic pathways involving natural polyphosphates, that may play a role in tau self-assembly.
阿尔茨海默病（AD）是一种多因素神经退行性疾病，其特征是进行性认知障碍、冷漠和神经精神障碍。已经描述了两种主要的病理特征：神经原纤维缠结，由 tau 寡聚物（过度磷酸化的 tau）和 Aβ斑块组成。蛋白激酶和磷酸酶对 tau 的过度磷酸化的影响已经为人所知。过度磷酸化的 tau 会发生构象变化，从而促进其自组装。然而，涉及这些机制的过程尚待阐明。体外重组 tau 可以通过多阴离子（如肝素、花生四烯酸，以及最近多磷酸盐）的作用聚集。然而，体内发生这种过程的方式尚不清楚。在这篇综述中，我们通过搜索该领域最准确和最新的文献，重点关注 tau 修饰、错误折叠及其病理自组装起始之间的精确分子事件。在这些事件中，我们可以确定 tau 磷酸化、tau 杂芳基化与自组装起始之间的联系以及涉及天然多磷酸盐的可能代谢途径等方面的挑战，这些可能在 tau 自组装中发挥作用。
