Seed-competent tau monomer initiates pathology in a tauopathy mouse model

Tau aggregation into ordered assemblies causes 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, that is, unique, self-replicating, biologically active assemblies. It is unknown if disease begins with M-s formation followed by fibril assembly or if M-s derives from fibrils and is therefore an epiphenomenon. Here, we studied a tauopathy mouse model (PS19) that expresses full-length mutant human (1N4R) tau (P301S). Insoluble tau seeding activity appeared at 2 months of age and insoluble tau protein assemblies by immunoblot at 3 months. Tau monomer from mice aged 1 to 6 weeks, purified using size-exclusion chromatography, contained soluble seeding activity at 4 weeks, before insoluble material or larger assemblies were observed, with assemblies ranging from n = 1 to 3 tau units. By 5 to 6 weeks, large soluble assemblies had formed. This indicated that the first detectable pathological forms of tau were in fact M-s. We next examined post-translational modifications of tau monomer from 1 to 6 weeks. We detected no phosphorylation unique to M-s in PS19 or human Alzheimer's disease brains. We conclude that tauopathy begins with formation of the M-s monomer, whose activity is phosphorylation independent. M-s then 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 the origins of tauopathy in humans.