Seed-competent tau monomer initiates pathology in PS19 tauopathy mice

Tau aggregation into ordered assemblies causes myriad neurodegenerative tauopathies. We previously reported that tau monomer exists in either inert (M i ) or seed-competent (M s ) conformational ensembles, and that M s encodes strains, which are biologically active, self-propagating assemblies. We have previously isolated M s from tauopathy brains, but it is unknown if disease begins with M s formation followed by fibril assembly, or if M s derives from fibrils and is an epiphenomenon. Consequently, we studied a tauopathy mouse model (PS19) that expresses full-length human (1N4R) tau containing a disease-associated mutation (P301S). Using tau repeat domain biosensor cells, we detected insoluble tau seeding activity at 2 months. We found insoluble tau protein assemblies by immunoblot at 3 months. We next immunopurified monomer from mice aged 1-6 weeks using size exclusion chromatography. We detected soluble seeding activity at 4 weeks, before insoluble material or larger assemblies, with assemblies ranging from n=1-3 tau units. By 5 and 6 weeks, large soluble assemblies had formed. This indicated the first detectable pathological forms of tau were M s . We next tested for post-translational modifications of tau monomer from 1-6 weeks. We detected no phosphorylation unique to M s in PS19 or Alzheimer’s disease brain. We conclude that tauopathy begins with formation of M s monomer, whose activity is phosphorylation-independent. M s self-assembles to form oligomers before it forms insoluble fibrils. The conversion of tau monomer from M i to M s thus constitutes the first detectable step in the initiation of tauopathy in this mouse model, with obvious implications for origins of disease in humans.