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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 (Mi) or seed-competent (Ms) conformational ensembles, and that Ms encodes strains, which are biologically active, self-propagating assemblies. We have previously isolated Ms from tauopathy brains, but it is unknown if disease begins with Ms formation followed by fibril assembly, or if Ms 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 Ms. We next tested for post-translational modifications of tau monomer from 1-6 weeks. We detected no phosphorylation unique to Ms in PS19 or Alzheimer’s disease brain. We conclude that tauopathy begins with formation of Ms monomer, whose activity is phosphorylation-independent. Ms self-assembles to form oligomers before it forms insoluble fibrils. The conversion of tau monomer from Mi to Ms thus constitutes the first detectable step in the initiation of tauopathy in this mouse model, with obvious implications for origins of disease in humans.