Distinct Tau Prion Strains Propagate in Cells and Mice and Define Different Tauopathies

Prion-like propagation of tau aggregation might underlie the stereotyped progression of neurodegenerative tauopathies. True prions stably maintain unique conformations (“strains”) in vivo that link structure to patterns of pathology. We now find that tau meets this criterion. Stably expressed tau repeat domain indefinitely propagates distinct amyloid conformations in a clonal fashion in culture. Reintroduction of tau from these lines into naive cells reestablishes identical clones. We produced two strains in vitro that induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Immunopurified tau from these mice recreates the original strains in culture. We used the cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with different sets of strains. Tau thus demonstrates essential characteristics of a prion. This might explain the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy. •Tau stably propagates multiple amyloid conformations (strains) in dividing cells•Strains induce unique pathologies in transgenic mice•Strains can be passaged through multiple generations of mice and back to cells•Different tauopathies are associated with different sets of strains Prions stably propagate unique conformations (strains) that produce different pathologies. Sanders et al. now report that tau acts as a prion in cells and in vivo by this criterion and find that different tauopathies are associated with unique tau strains.