Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease
The abnormal assembly of tau protein in neurons is a pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). Assembled tau associates with extracellular vesicles (EVs) in the central nervous system of individuals with AD, which is linked to its clearance and prion-like propagation. However, the identities of the assembled tau species and EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from individuals with AD. We found tau filaments composed mainly of truncated tau that were enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.
Authors
- Emir Turkes (ORCID: https://orcid.org/0000-0002-7447-1476)
- Martha Foiani (ORCID: https://orcid.org/0000-0003-4157-2606)
- Elena Ficulle
- Karen Duff (ORCID: https://orcid.org/0000-0002-6177-868X)
- Gerard Crowley (ORCID: https://orcid.org/0000-0003-0436-1332)
- Román Fischer (ORCID: https://orcid.org/0000-0002-9715-5951)
- Darragh P. O’Brien (ORCID: https://orcid.org/0000-0003-4924-7795)
- Sumi Bez (ORCID: https://orcid.org/0000-0002-8971-5103)
- Eliona Tsefou (ORCID: https://orcid.org/0000-0002-4643-2584)
- Efrat Levy (ORCID: https://orcid.org/0000-0001-6890-6763)
- Ari W. Schaler (ORCID: https://orcid.org/0000-0003-2504-220X)
- Bethany Geary (ORCID: https://orcid.org/0000-0002-5592-5532)
- Tiana S. Behr (ORCID: https://orcid.org/0000-0001-8832-8411)
- Pallavi Gaur (ORCID: https://orcid.org/0000-0002-0286-1950)
- Stephanie L. Fowler (ORCID: https://orcid.org/0000-0001-6693-9959)
- Megan C. Edmonds (ORCID: https://orcid.org/0000-0002-0928-3858)
- Chelsea Miller
- Pasquale D’Acunzo (ORCID: https://orcid.org/0000-0001-7237-0076)
- Benjamin Falcon (ORCID: https://orcid.org/0000-0002-8176-2618)
- Paula Maglio Cauhy (ORCID: https://orcid.org/0000-0003-1004-3656)
- Isadora Rawlinson
Institutions
- Nathan Kline Institute for Psychiatric Research (US)
- Hackensack University Medical Center (US)
- MRC Laboratory of Molecular Biology (GB)
- University of Dundee (GB)
- Columbia University Irving Medical Center (US)
- University of Oxford (GB)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- UK Dementia Research Institute (GB)
- University College London (GB)
- New York University (US)
- Medical Research Council (GB)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1038/s41593-024-01801-5
- Citations
- 63
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 14.50
Funders
- Alzheimer's Association
- BrightFocus Foundation
- Alzheimer’s Research UK
- National Institutes of Health
- Medical Research Council