Mechanistic Studies Unravel the Complexity Inherent in Tau Aggregation Leading to Alzheimer’s Disease and the Tauopathies

The aggregation of the protein tau into amyloid fibrils is known to be involved in the causation of the neurodegenerative tauopathies and the progression of cognitive decline in Alzheimer’s disease. This review surveys the mechanism of tau aggregation with special emphasis on the information obtained from biochemical and biophysical studies. First, tau is described from a structure–function perspective. Subsequently, the connection of tau to neurodegeneration is explained, and a description of the tau amyloid fibril is provided. Lastly, studies of the mechanism of tau fibril formation are reviewed, and the physiological significance of these studies with reference to how they can clarify many aspects of disease progression is described. The aim of this review is to underscore how mechanistic studies reveal the complexity of the tau fibril formation pathway and the plethora of species populated on or off the pathway of aggregation, and how this information can be beneficial in the design of inhibitors or drugs that ameliorate neurodegeneration.