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TitleTau filaments are tethered within brain extracellular vesicles in Alzheimer's disease.
Journal, issue, pagesbioRxiv, Year 2023
Publish dateApr 30, 2023
AuthorsS L Fowler / T S Behr / E Turkes / P Maglio Cauhy / M S Foiani / A Schaler / G Crowley / S Bez / E Ficulle / E Tsefou / D P O'Brien / R Fischer / B Geary / P Gaur / C Miller / P D'Acunzo / E Levy / K E Duff / B Ryskeldi-Falcon
PubMed AbstractThe abnormal assembly of tau protein in neurons is the pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). In addition, assembled tau associates with ...The abnormal assembly of tau protein in neurons is the pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). In addition, assembled tau associates with extracellular vesicles (EVs) in the central nervous system of patients with AD, which is linked to its clearance and prion-like propagation between neurons. However, the identities of the assembled tau species and the 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 AD patients. We found filaments of truncated tau 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.
External linksbioRxiv / PubMed:37163117 / PubMed Central
MethodsEM (helical sym.) / EM (tomography)
Resolution3.16 - 3.27 Å
Structure data

16035

8bgs

EMDB-16035: Tau Paired Helical Filament from Extracellular Vesicles from Alzheimer's disease brain (Individual 1)
PDB-8bgs: Tau Paired Helical Filament from Extracellular Vesicles from Alzheimer's disease brain
Method: EM (helical sym.) / Resolution: 3.16 Å

16039

8bgv

EMDB-16039, PDB-8bgv:
Tau Paired Helical Filament from Cellular Fraction of Alzheimer's disease brain
Method: EM (helical sym.) / Resolution: 3.27 Å

EMDB-16064: Cryo-electron tomogram of an extracellular vesicle containing tau filaments isolated from Alzheimer's Disease patient brain
Method: EM (tomography)

Source
  • homo sapiens (human)
  • human (human)
KeywordsPROTEIN FIBRIL / AMYLOID

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