4R-tau seeding activity reveals molecular subtypes in progressive supranuclear palsy
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.
Authors
- Ali Mohammadi Karakani
- Fernandez‐Irigoyen Joaquin
- Hidetomo Tanaka
- Gábor G. Kovács
- Ain Kim (ORCID: https://orcid.org/0009-0005-3810-6390)
- Seojin Lee (ORCID: https://orcid.org/0000-0003-2827-1091)
- Susan H. Fox (ORCID: https://orcid.org/0000-0003-4779-4269)
- Syeda Hania Qamar (ORCID: https://orcid.org/0009-0008-4855-1860)
- Blas Couto
- Tallulah Andrews (ORCID: https://orcid.org/0000-0003-1120-2196)
- Shelley L. Forrest
- Silvia Zampar (ORCID: https://orcid.org/0000-0003-0134-0974)
- Ekaterina Rogaeva
- Konstantin Senkevich
- Enrique Santamaria
- Anthony E. Lang
- Nikolai Gil D. Reyes
- Ivan Martinez-Valbuena
- Jun Li
- M. Carmela Tartaglia
- Naomi P. Visanji
- Martin Ingelsson
Institutions
- Uppsala University (SE)
- Western University (CA)
- Montreal Neurological Institute and Hospital (CA)
- University Health Network (CA)
- Universidad Pública de Navarra (UPNA) (ES)
- University of Toronto (CA)
- Toronto Western Hospital (CA)
- Occupational Cancer Research Centre (CA)
- Navarre Institute of Health Research (ES)
- Navarrabiomed (ES)
- Instituto de Neurología Cognitiva (AR)
- Ontario Brain Institute (CA)
- McGill University (CA)
- Macquarie University (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-31
- DOI
- https://doi.org/10.1038/s41467-025-67744-y
- Citations
- 1
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.16
Funders
- Edmond J. Safra Philanthropic Foundation
- Krembil Foundation
- National Institutes of Health
- Agencia Estatal de Investigación