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 posttranslational 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.