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

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.

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References
1.
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

2.
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

3.
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

4.
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

5.
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