Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo

Tauopathies are neurodegenerative disorders that affect distinct brain regions, progress at different rates, and exhibit specific patterns of tau accumulation. The source of this diversity is unknown. We previously characterized two tau strains that stably maintain unique conformations in vitro and in vivo, but did not determine the relationship of each strain to parameters that discriminate between tauopathies such as regional vulnerability or rate of spread. We have now isolated and characterized 18 tau strains in cells based on detailed biochemical and biological criteria. Inoculation of PS19 transgenic tau (P301S) mice with these strains causes strain-specific intracellular pathology in distinct cell types and brain regions, and induces different rates of network propagation. In this system, strains alone are sufficient to account for diverse neuropathological presentations, similar to those that define human tauopathies. Further study of these strains can thus establish a structural logic that governs these biological effects. •Tau forms multiple, unique prion strains with distinct biochemical properties•Tau strains induce diverse pathological phenotypes in vitro and in vivo•Tau strains target different brain regions and propagate pathology at unique rates•We present a framework to understand the diversity of human tauopathies Kaufman et al. observe that tau forms multiple self-propagating amyloid strains. The introduction of each into transgenic mouse brain creates a distinct pathology that targets different brain regions and induces unique rates of spread. Thus, strain variation can account for the diversity of human tauopathies.