The Structure Biology of Tau and Clue for Aggregation Inhibitor Design

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.