Extracellular Vesicles: Major Actors of Heterogeneity in Tau Spreading Among Human Tauopathies

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2021 Sep 26

PMID 34563677

Citations 17

Authors

Elodie Leroux

Romain Perbet

Raphaelle Caillierez

Kevin Richetin

Sarah Lieger

Jeanne Espourteille

Thomas Bouillet

Severine Begard

Clement Danis

Anne Loyens

Nicolas Toni

Nicole Deglon

Vincent Deramecourt

Susanna Schraen-Maschke

Luc Buee

Morvane Colin

Affiliations

Soon will be listed here.

Abstract

Tauopathies are neurodegenerative diseases characterized by tau inclusions in brain cells. Seed-competent tau species have been suggested to spread from cell to cell in a stereotypical manner, indicating that this may involve a prion-like mechanism. Although the intercellular mechanisms of transfer are unclear, extracellular vesicles (EVs) could be potential shuttles. We assessed this in humans by preparing vesicles from fluids (brain-derived enriched EVs [BD-EVs]). These latter were isolated from different brain regions in various tauopathies, and their seeding potential was assessed in vitro and in vivo. We observed considerable heterogeneity among tauopathies and brain regions. The most striking evidence was coming mainly from Alzheimer's disease where the BD-EVs clearly contain pathological species that can induce tau lesions in vivo. The results support the hypothesis that BD-EVs participate in the prion-like propagation of tau pathology among tauopathies, and there may be implications for diagnostic and therapeutic strategies.

Citing Articles

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

Fowler S, Behr T, Turkes E, OBrien D, Cauhy P, Rawlinson I Nat Neurosci. 2024; 28(1):40-48.

PMID: 39572740 PMC: 11706778. DOI: 10.1038/s41593-024-01801-5.

Arc mediates intercellular tau transmission via extracellular vesicles.

Tyagi M, Chadha R, de Hoog E, Sullivan K, Walker A, Northrop A bioRxiv. 2024; .

PMID: 39484489 PMC: 11526995. DOI: 10.1101/2024.10.22.619703.

TMEM16F exacerbates tau pathology and mediates phosphatidylserine exposure in phospho-tau-burdened neurons.

Zubia M, Yong A, Holtz K, Huang E, Jan Y, Jan L Proc Natl Acad Sci U S A. 2024; 121(27):e2311831121.

PMID: 38941274 PMC: 11228522. DOI: 10.1073/pnas.2311831121.

In situ seeding assay: A novel technique for direct tissue localization of bioactive tau.

Perbet R, Mate de Gerando A, Glynn C, Donahue C, Gaona A, Taddei R J Neuropathol Exp Neurol. 2024; 83(10):870-881.

PMID: 38917443 PMC: 11413465. DOI: 10.1093/jnen/nlae059.

Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS.

Chatterjee M, Ozdemir S, Fritz C, Mobius W, Kleineidam L, Mandelkow E Nat Med. 2024; 30(6):1771-1783.

PMID: 38890531 PMC: 11186765. DOI: 10.1038/s41591-024-02937-4.

References

Jeganathan S, Hascher A, Chinnathambi S, Biernat J, Mandelkow E, Mandelkow E . Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC-1) conformation. J Biol Chem. 2008; 283(46):32066-76. DOI: 10.1074/jbc.M805300200. View

Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S . Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem. 2011; 287(6):3842-9. PMC: 3281682. DOI: 10.1074/jbc.M111.277061. View

Deramecourt V, Lebert F, Maurage C, Fernandez-Gomez F, Dujardin S, Colin M . Clinical, neuropathological, and biochemical characterization of the novel tau mutation P332S. J Alzheimers Dis. 2012; 31(4):741-9. DOI: 10.3233/JAD-2012-120160. View

Winston C, Aulston B, Rockenstein E, Adame A, Prikhodko O, Dave K . Neuronal Exosome-Derived Human Tau is Toxic to Recipient Mouse Neurons in vivo. J Alzheimers Dis. 2018; 67(2):541-553. PMC: 8373009. DOI: 10.3233/JAD-180776. View

Yoshida H, Goedert M . Sequential phosphorylation of tau protein by cAMP-dependent protein kinase and SAPK4/p38delta or JNK2 in the presence of heparin generates the AT100 epitope. J Neurochem. 2006; 99(1):154-64. DOI: 10.1111/j.1471-4159.2006.04052.x. View

Tyanova S, Temu T, Sinitcyn P, Carlson A, Hein M, Geiger T . The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods. 2016; 13(9):731-40. DOI: 10.1038/nmeth.3901. View

Jia L, Qiu Q, Zhang H, Chu L, Du Y, Zhang J . Concordance between the assessment of Aβ42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement. 2019; 15(8):1071-1080. DOI: 10.1016/j.jalz.2019.05.002. View

Maas S, Breakefield X, Weaver A . Extracellular Vesicles: Unique Intercellular Delivery Vehicles. Trends Cell Biol. 2016; 27(3):172-188. PMC: 5318253. DOI: 10.1016/j.tcb.2016.11.003. View

Polanco J, Hand G, Briner A, Li C, Gotz J . Exosomes induce endolysosomal permeabilization as a gateway by which exosomal tau seeds escape into the cytosol. Acta Neuropathol. 2021; 141(2):235-256. PMC: 7847444. DOI: 10.1007/s00401-020-02254-3. View

10.

Kaufman S, Sanders D, Thomas T, Ruchinskas A, Vaquer-Alicea J, Sharma A . Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo. Neuron. 2016; 92(4):796-812. PMC: 5392364. DOI: 10.1016/j.neuron.2016.09.055. View

11.

Sotiropoulos I, Galas M, Silva J, Skoulakis E, Wegmann S, Maina M . Atypical, non-standard functions of the microtubule associated Tau protein. Acta Neuropathol Commun. 2017; 5(1):91. PMC: 5707803. DOI: 10.1186/s40478-017-0489-6. View

12.

Holmes B, Furman J, Mahan T, Yamasaki T, Mirbaha H, Eades W . Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci U S A. 2014; 111(41):E4376-85. PMC: 4205609. DOI: 10.1073/pnas.1411649111. View

13.

Fitzpatrick A, Falcon B, He S, Murzin A, Murshudov G, Garringer H . Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017; 547(7662):185-190. PMC: 5552202. DOI: 10.1038/nature23002. View

14.

Ruan Z, Pathak D, Kalavai S, Yoshii-Kitahara A, Muraoka S, Bhatt N . Alzheimer's disease brain-derived extracellular vesicles spread tau pathology in interneurons. Brain. 2020; 144(1):288-309. PMC: 7880668. DOI: 10.1093/brain/awaa376. View

15.

Forrest S, Kril J, Stevens C, Kwok J, Hallupp M, Kim W . Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. Brain. 2017; 141(2):521-534. PMC: 5888940. DOI: 10.1093/brain/awx328. View

16.

Guix F, Corbett G, Cha D, Mustapic M, Liu W, Mengel D . Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. Int J Mol Sci. 2018; 19(3). PMC: 5877524. DOI: 10.3390/ijms19030663. View

17.

Dujardin S, Begard S, Caillierez R, Lachaud C, Carrier S, Lieger S . Different tau species lead to heterogeneous tau pathology propagation and misfolding. Acta Neuropathol Commun. 2018; 6(1):132. PMC: 6263555. DOI: 10.1186/s40478-018-0637-7. View

18.

Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-59. DOI: 10.1007/BF00308809. View

19.

Richetin K, Steullet P, Pachoud M, Perbet R, Parietti E, Maheswaran M . Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer's disease. Nat Neurosci. 2020; 23(12):1567-1579. DOI: 10.1038/s41593-020-00728-x. View

20.

Wang Y, Biernat J, Pickhardt M, Mandelkow E, Mandelkow E . Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Proc Natl Acad Sci U S A. 2007; 104(24):10252-7. PMC: 1891218. DOI: 10.1073/pnas.0703676104. View