PROJECT SUMMARY Tau aggregation is a shared pathology of Alzheimer's disease and related dementias known as tauopathies. Despite commonalities in aggregation mechanism, each disorder develops unique filamentous morphologies that reflect differential vulnerability of their constituent cell populations. In addition to providing clues about the cellular conditions associated with tauopathic neurodegeneration, the appearance of unique polymorphs in each tauopathy implicates prion-like mechanisms of templating and spread that may influence the course and severity of disease. As a result, aggregate polymorphism is a potential target for therapeutic intervention as well as for differential diagnosis of tauopathies through development of whole-brain imaging methods. This proposal seeks to advance these goals by clarifying mechanisms underlying aggregate nucleation, propagation and interaction with small-molecule probes using biochemical and structural biological approaches. Specifically it aims to (1) determine the effects of aggregation inducers including tau phosphorylation on polymorph formation, (2) clarify mechanisms through which nucleation sequence motifs common to all tau isoforms trigger aggregation, (3) rigorously test whether tau polymorphism can propagate through prion-like seeding mechanisms, and (4) identify molecular interactions that mediate the binding affinity and selectivity of tau-aggregate directed ligands. Accomplishing these goals will clarify the molecular basis of tauopathy pathogenesis and catalyze efforts toward creating novel diagnostic strategies tailored toward individual tau aggregate polymorphs.