4R-tau seeding activity reveals molecular subtypes in progressive supranuclear palsy.

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

SUBMITTER: Martinez-Valbuena I 

PROVIDER: S-EPMC12847749 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature