Tau from SPAM Transgenic Mice Exhibit Potent Strain-Specific Prion-Like Seeding Properties Characteristic of Human Neurodegenerative Diseases.

Tauopathies, including Alzheimer's disease and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), are characterized by the aberrant aggregation of tau protein into neurofibrillary tangles. Despite extensive studies on tau aggregation, the mechanisms of tau misfolding and propagation remain incompletely understood. In this study, we utilize the SPAM (S320F/P301S) tau transgenic mouse model, which expresses 0N4R human tau with two FTDP-17 mutations, to investigate the biochemical properties and seeding potential of misfolded tau from these mice. Sarkosyl extraction and ultracentrifugation were employed to isolate detergent-insoluble tau aggregates (SPAM-tau) from aged SPAM mice. These aggregates were then tested for their prion-type seeding activity in an established HEK293T cell model comparing the induced aggregation of wild-type and mutant forms of human and murine tau. Our results show that SPAM-tau exhibits distinct and vigorous prion-like seeding properties, inducing the aggregation of human and murine tau homologues with the formation of amyloidogenic (Thioflavin S-positive) inclusions. Importantly, SPAM-tau aggregates can facilitate the prion-type misfolding of wild-type and mutant forms of human and mouse tau. We demonstrated that these induced tau aggregates are able to be further transmitted in passaging studies. Furthermore, SPAM-tau preferentially templated 4R tau isoforms, sharing strain-like seeding properties with insoluble tau derived from the brains of individuals with progressive supranuclear palsy (PSP-tau). In summary, these findings enhance our understanding of tau aggregation and propagation, suggesting that SPAM-tau may serve as a valuable tool for studying tauopathies and evaluating potential therapeutic strategies aimed at halting tau misfolding and propagation.