4R-Tau Seeding Activity Reveals Molecular Subtypes in Progressive Supranuclear Palsy

Progressive Supranuclear Palsy (PSP) is a clinically heterogeneous 4-repeat (4R)-tauopathy marked by variable progression and phenotypic diversity. We examined the distribution of high-molecular-weight tau (HMW-tau) species and 4R-tau seeding capacity across 25 PSP cases and 20 brain regions. HMW-tau levels varied regionally, with the temporal and motor cortices exhibiting the highest abundance. Using size-exclusion chromatography (SEC) and 4R-tau seed amplification assays (SAAs), we identified that HMW-tau fractions exhibit the greatest seeding activity. Proteomic and spatial transcriptomic analyses of the primary motor cortex revealed dysregulated adaptive immunity and metabolic pathways in high-seeder cases. Neuropathological clustering confirmed distinct profiles associated with tau seeding activity. These findings suggest that evaluating tau seeding capacity may offer valuable insights into the heterogeneity of PSP and its underlying molecular drivers. Overall design: Post-mortem tissue sections from the motor cortex of four patients with Progressive Supranuclear Palsy (PSP) (2 high seeders, 2 low seeders) were selected for spatial transcriptomics based on distinct 4R-tau seeding capacities identified via seed amplification assays. These cases showed comparable PSP stage, phenotype, and co-pathologies. They were also used in neuropathological and proteomic analyses. Tissue quality (DV200?>?50%) ensured suitability for Visium profiling.