Tau filaments are tethered within brain extracellular vesicles in Alzheimer's disease

Stephanie L Fowler; Tiana S Behr; Emir Turkes; Darragh P O'Brien; Paula Maglio Cauhy; Isadora Rawlinson; Marisa Edmonds; Martha S Foiani; Ari Schaler; Gerard Crowley; Sumi Bez; Elena Ficulle; Eliona Tsefou; Roman Fischer; Beth Geary; Pallavi Gaur; Chelsea Miller; Pasquale D'Acunzo; Efrat Levy; Karen E Duff; Benjamin Ryskeldi-Falcon

doi:10.1038/s41593-024-01801-5

Tau filaments are tethered within brain extracellular vesicles in Alzheimer's disease

Nat Neurosci. 2024 Nov 21. doi: 10.1038/s41593-024-01801-5. Online ahead of print.

Authors

Stephanie L Fowler^#^{1

2}, Tiana S Behr^#³, Emir Turkes¹, Darragh P O'Brien⁴, Paula Maglio Cauhy¹, Isadora Rawlinson³, Marisa Edmonds¹, Martha S Foiani¹, Ari Schaler⁵, Gerard Crowley¹, Sumi Bez¹, Elena Ficulle¹, Eliona Tsefou¹, Roman Fischer⁴, Beth Geary⁶, Pallavi Gaur⁷, Chelsea Miller^{8

9}, Pasquale D'Acunzo^{9

10}, Efrat Levy^{9

10

11

12}, Karen E Duff^{13

14}, Benjamin Ryskeldi-Falcon¹⁵

Affiliations

¹ UK Dementia Research Institute at University College London, London, UK.
² Oxford-GSK Institute of Molecular and Computational Medicine, University of Oxford, Oxford, UK.
³ Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
⁴ Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁵ Taub Institute, Irving Medical Center, Columbia University, New York, NY, USA.
⁶ Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
⁷ Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA.
⁸ The Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, NJ, USA.
⁹ Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
¹⁰ Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA.
¹¹ Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.
¹² Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA.
¹³ UK Dementia Research Institute at University College London, London, UK. k.duff@ucl.ac.uk.
¹⁴ Taub Institute, Irving Medical Center, Columbia University, New York, NY, USA. k.duff@ucl.ac.uk.
¹⁵ Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. bfalcon@mrc-lmb.cam.ac.uk.

^# Contributed equally.

PMID: 39572740
DOI: 10.1038/s41593-024-01801-5

Abstract

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.

Abstract

Grants and funding