Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease
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 c...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Internet publication |
| Language: | English |
| Published: |
2023
|
| _version_ | 1797112811916099584 |
|---|---|
| author | Fowler, SL Behr, TS Turkes, E Cauhy, PM Foiani, MS Schaler, A Crowley, G Bez, S Ficulle, E Tsefou, E O'Brien, DP Fischer, R Geary, B Gaur, P Miller, C D'Acunzo, P Levy, E Duff, KE Ryskeldi-Falcon, B |
| author_facet | Fowler, SL Behr, TS Turkes, E Cauhy, PM Foiani, MS Schaler, A Crowley, G Bez, S Ficulle, E Tsefou, E O'Brien, DP Fischer, R Geary, B Gaur, P Miller, C D'Acunzo, P Levy, E Duff, KE Ryskeldi-Falcon, B |
| author_sort | Fowler, SL |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T08:24:40Z |
| format | Internet publication |
| id | oxford-uuid:6b5be056-6305-4bfb-9708-cdf0140873e4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-04-09T03:54:45Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:6b5be056-6305-4bfb-9708-cdf0140873e42024-03-08T16:55:55ZTau filaments are tethered within brain extracellular vesicles in Alzheimer’s diseaseInternet publicationhttp://purl.org/coar/resource_type/c_7ad9uuid:6b5be056-6305-4bfb-9708-cdf0140873e4EnglishSymplectic Elements2023Fowler, SLBehr, TSTurkes, ECauhy, PMFoiani, MSSchaler, ACrowley, GBez, SFiculle, ETsefou, EO'Brien, DPFischer, RGeary, BGaur, PMiller, CD'Acunzo, PLevy, EDuff, KERyskeldi-Falcon, BThe 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. |
| spellingShingle | Fowler, SL Behr, TS Turkes, E Cauhy, PM Foiani, MS Schaler, A Crowley, G Bez, S Ficulle, E Tsefou, E O'Brien, DP Fischer, R Geary, B Gaur, P Miller, C D'Acunzo, P Levy, E Duff, KE Ryskeldi-Falcon, B Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease |
| title | Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease |
| title_full | Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease |
| title_fullStr | Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease |
| title_full_unstemmed | Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease |
| title_short | Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease |
| title_sort | tau filaments are tethered within brain extracellular vesicles in alzheimer s disease |
| work_keys_str_mv | AT fowlersl taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT behrts taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT turkese taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT cauhypm taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT foianims taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT schalera taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT crowleyg taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT bezs taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT ficullee taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT tsefoue taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT obriendp taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT fischerr taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT gearyb taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT gaurp taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT millerc taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT dacunzop taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT levye taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT duffke taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease AT ryskeldifalconb taufilamentsaretetheredwithinbrainextracellularvesiclesinalzheimersdisease |