Evidence for trans-synaptic propagation of oligomeric tau in human progressive supranuclear palsy
In the neurodegenerative disease progressive supranuclear palsy (PSP), tau pathology progresses through the brain in a stereotypical spatiotemporal pattern, and where tau pathology appears, synapses are lost. We tested the hypothesis that pathological tau contributes to synapse loss and may spread through the brain by moving from presynapses to postsynapses. Using postmortem PSP brain samples and a living human brain slice culture model, we observe pathological tau in synaptic pairs and evidence that oligomeric tau can enter live human postsynapses. Proteomics revealed increased clusterin in synapses in PSP, and super-resolution imaging showed clusterin colocalized with tau in synapses in close enough proximity to be binding partners, which may mediate tau spread. Accumulation of tau in synapses correlated with synapse loss, and synaptic engulfment by astrocytes was observed, suggesting that astrocytes contribute to synapse loss. Together, these data indicate that targeting synaptic tau is a promising approach to treat PSP.
Authors
- Claire S. Durrant (ORCID: https://orcid.org/0000-0001-7552-7358)
- Jamie Rose (ORCID: https://orcid.org/0000-0002-8110-376X)
- Imran Liaquat
- Cristina Scutariu
- Jane Tulloch (ORCID: https://orcid.org/0009-0005-6975-5430)
- Makis Tzioras (ORCID: https://orcid.org/0000-0002-2660-5943)
- Ya Yin Chang (ORCID: https://orcid.org/0000-0001-9794-403X)
- Kristján Holt (ORCID: https://orcid.org/0000-0003-3903-6361)
- Sam A. Booker (ORCID: https://orcid.org/0000-0003-1980-9873)
- Robert I. McGeachan (ORCID: https://orcid.org/0000-0003-1647-8642)
- Elizabeth Simzer (ORCID: https://orcid.org/0000-0002-7043-1450)
- Bethany Geary (ORCID: https://orcid.org/0000-0002-5592-5532)
- Declan King (ORCID: https://orcid.org/0000-0002-2434-9317)
- Colin Smith (ORCID: https://orcid.org/0000-0002-4507-5132)
- S. Meftah (ORCID: https://orcid.org/0000-0002-3408-5626)
- Paul Martin Brennan (ORCID: https://orcid.org/0000-0002-7347-830X)
- Maxwell P Spires-Jones (ORCID: https://orcid.org/0000-0003-2616-2182)
- Tara L. Spires‐Jones (ORCID: https://orcid.org/0000-0003-2530-0598)
- Lois Keavey (ORCID: https://orcid.org/0009-0008-1492-2678)
- Natalia Ravingerova
- Lewis W. Taylor (ORCID: https://orcid.org/0009-0002-2531-6696)
- Margaret Gilmore
- Nicole Hindley-Pollock
Institutions
- University of Dundee (GB)
- Discovery Centre (CA)
- MRC Centre for Regenerative Medicine (GB)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- UK Dementia Research Institute (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1038/s41593-025-01992-5
- Citations
- 13
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 11.82
Funders
- Wellcome
- Dyson Foundation
- Alzheimer’s Research UK
- UK Dementia Research Institute