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

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 (Lead / Corresponding author)Benjamin Ryskeldi-Falcon (Lead / Corresponding author)

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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.

Original language	English
Article number	9477
Pages (from-to)	40-48
Number of pages	9
Journal	Nature Neuroscience
Volume	28
Issue number	1
Early online date	21 Nov 2024
DOIs	https://doi.org/10.1038/s41593-024-01801-5
Publication status	Published - Jan 2025

ASJC Scopus subject areas

General Neuroscience

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Final Published VersionFinal published version, 16.6 MBLicence: CC BY

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Fowler, S. L., Behr, T. S., Turkes, E., O’Brien, D. P., Cauhy, P. M., Rawlinson, I., Edmonds, M., Foiani, M. S., Schaler, A., Crowley, G., Bez, S., Ficulle, E., Tsefou, E., Fischer, R., Geary, B., Gaur, P., Miller, C., D’Acunzo, P., Levy, E., ... Ryskeldi-Falcon, B. (2025). Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease. Nature Neuroscience, 28(1), 40-48. Article 9477. https://doi.org/10.1038/s41593-024-01801-5

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title = "Tau filaments are tethered within brain extracellular vesicles in Alzheimer{\textquoteright}s disease",

abstract = "The abnormal assembly of tau protein in neurons is a pathological hallmark of multiple neurodegenerative diseases, including Alzheimer{\textquoteright}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.",

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

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year = "2025",

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doi = "10.1038/s41593-024-01801-5",

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Fowler, SL, Behr, TS, Turkes, E, O’Brien, DP, Cauhy, PM, Rawlinson, I, Edmonds, M, Foiani, MS, Schaler, A, Crowley, G, Bez, S, Ficulle, E, Tsefou, E, Fischer, R, Geary, B, Gaur, P, Miller, C, D’Acunzo, P, Levy, E, Duff, KE & Ryskeldi-Falcon, B 2025, 'Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease', Nature Neuroscience, vol. 28, no. 1, 9477, pp. 40-48. https://doi.org/10.1038/s41593-024-01801-5

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AU - Fowler, Stephanie L.

AU - Behr, Tiana S.

AU - Turkes, Emir

AU - O’Brien, Darragh P.

AU - Cauhy, Paula Maglio

AU - Rawlinson, Isadora

AU - Edmonds, Marisa

AU - Foiani, Martha S.

AU - Schaler, Ari

AU - Crowley, Gerard

AU - Bez, Sumi

AU - Ficulle, Elena

AU - Tsefou, Eliona

AU - Fischer, Roman

AU - Geary, Beth

AU - Gaur, Pallavi

AU - Miller, Chelsea

AU - D’Acunzo, Pasquale

AU - Levy, Efrat

AU - Duff, Karen E.

AU - Ryskeldi-Falcon, Benjamin

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AB - 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.

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IS - 1

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ER -

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

Abstract

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