4R-tau seeding activity reveals molecular subtypes in progressive supranuclear palsy
Ivan Martinez-Valbuena, Seojin Lee, Enrique Santamaría, Fernandez-Irigoyen Joaquin, Shelley L. Forrest, Silvia Zampar, J. -Y. Li, Hidetomo Tanaka, Blas Couto, Nikolai Gil D. Reyes, Syeda Hania Qamar, Ali Mohammadi Karakani, Ain Kim, Konstantin Senkevich, Ekaterina Rogaeva, Susan H. Fox, M. Carmela Tartaglia, Naomi P. Visanji, Martin Ingelsson, Tallulah Andrews, Anthony E. Lang, Gábor G. Kovács
Abstract
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by abnormal accumulation of the protein tau in the brain, leading to motor and cognitive symptoms that vary between individuals. The reasons for this clinical heterogeneity are unknown. Here we show that distinct molecular forms of tau, particularly high molecular weight (HMW) assemblies, differ in abundance and biological activity across PSP brains. By combining biochemical examination, seed amplification assays, proteomic profiling, and spatial transcriptomics, we identify that HMW tau species drive the strongest aggregation activity in the primary motor cortex. Cases with high tau seeding activity display molecular signatures of altered immune and metabolic pathways. These findings reveal that tau seeding activity reflects underlying molecular heterogeneity in PSP and suggest that measuring 4R-tau seeding capacity could help stratify patients and guide the development of targeted therapeutic approaches. This study shows that high-molecular weight tau has enhanced seeding capacity, and seeding differences can define molecular subtypes of progressive supranuclear palsy, underpinning the disease’s heterogeneity.