The ordered assembly of tau is the gain-of-toxic function that causes human tauopathies.

A pathological pathway leading from soluble to insoluble and filamentous tau underlies human tauopathies. This ordered assembly causes disease and is the gain-of-toxic function. It involves the transition from an intrinsically disordered monomer to a highly structured filament. Based on recent findings, one can divide the ordered assembly into propagation of pathology and neurodegeneration. Short tau fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S tau. The molecular species of aggregated tau that are essential for neurodegeneration remain to be identified.