Tau is a microtubule-associated protein that is mainly expressed in central and peripheral nerve systems. Tau binds to tubulin and regulates assembly and stabilization of microtubule, thus playing a critical role in neuron morphology, axon development and navigation. Tau is highly stable under normal conditions; however, there are several factors that can induce or promote aggregation of tau, forming neurofibrillary tangles. Neurofibrillary tangles are toxic to neurons, which may be related to a series of neurodegenerative diseases including Alzheimer’s disease. Thus, tau is widely accepted as an important therapeutic target for neurodegenerative diseases. While the monomeric structure of tau is highly disordered, the aggregate structure of tau is formed by closed packing of β-stands. Studies on the structure of tau and the structural transition mechanism provide valuable information on the occurrence, development, and therapy of tauopathies. In this review, we summarize recent progress on the structural investigation of tau and based on which we discuss aggregation inhibitor design.

Tau 是一种微管相关蛋白，主要在中枢和外周神经系统中表达。Tau 与微管蛋白结合并调节微管的组装和稳定，从而在神经元形态、轴突发育和导航中发挥关键作用。Tau 在正常条件下高度稳定；然而，有几个因素可以诱导或促进 tau 的聚集，形成神经原纤维缠结。神经原纤维缠结对神经元具有毒性，这可能与包括阿尔茨海默病在内的一系列神经退行性疾病有关。因此，tau 被广泛接受为神经退行性疾病的重要治疗靶点。虽然 tau 的单体结构高度无序，但 tau 的聚集结构是由 β-链的封闭堆积形成的。tau 蛋白的结构和结构转变机制的研究为 tau 蛋白病的发生、发展和治疗提供了有价值的信息。在这篇综述中，我们总结了 tau 结构研究的最新进展，并在此基础上讨论了聚集抑制剂的设计。