Abstract
Tauopathies are defined by progressive accumulation of tau amyloids. These assemble around a protein seed, whose structure is unknown, but might explain the initiation of pathology. We have purified and characterized distinct forms of tau monomer—either seed-competent or inert. Recombinant tau that was seed-competent triggered intracellular tau aggregation, induced full length tau fibrillization in vitro, and exhibited intrinsic properties of self-assembly. Tau monomer from AD brain, but not from controls, similarly seeded aggregation, and self-assembled in vitro to form higher order, seed-competent structures. We used crosslinking with mass spectrometry to identify distinct conformers of both recombinant tau and human brain-derived protein. Theoretical models informed by this data suggest that VQIINK and VQIVYK sequences, which support amyloid formation, are uniquely exposed in all seed-competent structures. Our data imply that initiation of pathological aggregation begins with conversion of tau monomer from an inert to a seed-competent form.