Extracellular vesicles: Major actors of heterogeneity in tau spreading among human tauopathies.

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.

Tau Transfer via Extracellular Vesicles Disturbs the Astrocytic Mitochondrial System.

Tauopathies are neurodegenerative disorders involving the accumulation of tau isoforms in cell subpopulations such as astrocytes. The origins of the 3R and 4R isoforms of tau that accumulate in astrocytes remain unclear. Extracellular vesicles (EVs) were isolated from primary neurons overexpressing 1N3R or 1N4R tau or from human brain extracts (progressive supranuclear palsy or Pick disease patients or controls) and characterized (electron microscopy, nanoparticle tracking analysis (NTA), proteomics). After the isolated EVs were added to primary astrocytes or human iPSC-derived astrocytes, tau transfer and mitochondrial system function were evaluated (ELISA, immunofluorescence, MitoTracker staining). We demonstrated that neurons in which 3R or 4R tau accumulated had the capacity to transfer tau to astrocytes and that EVs were essential for the propagation of both isoforms of tau. Treatment with tau-containing EVs disrupted the astrocytic mitochondrial system, altering mitochondrial morphology, dynamics, and redox state. Although similar levels of 3R and 4R tau were transferred, 3R tau-containing EVs were significantly more damaging to astrocytes than 4R tau-containing EVs. Moreover, EVs isolated from the brain fluid of patients with different tauopathies affected mitochondrial function in astrocytes derived from human iPSCs. Our data indicate that tau pathology spreads to surrounding astrocytes via EVs-mediated transfer and modifies their function.

[Extracellular vesicles in the central nervous system]. / Les vésicules extracellulaires - Actrices de la communication entre les cellules du système nerveux.

Extracellular Vesicles (EVs) are released by a wide diversity of cells. They contain proteins, RNAs and lipids that will be exchanged between these cells. They represent therefore a major form of intercellular communication in both physiological and pathological conditions. This is particularly relevant in the nervous system where neurons and glial cells form a very dense network where billions of connections are made. In this review, the different roles played by the EVs in a healthy brain to maintain cerebral homeostasis during development, synaptic transmission or axonal myelination will be discussed. In addition, the pathological aspects of EVs presence will also be addressed. In recent years, the EVs have emerged as major players in the spread of neurodegenerative diseases, in neuroinflammation and in tumor development, although they may also be beneficial in some conditions.

TITLE: Les vésicules extracellulaires - Actrices de la communication entre les cellules du système nerveux. ABSTRACT: Les vésicules extracellulaires (VE) sont libérées par une grande variété de cellules et contiennent des protéines, des ARN et des lipides, qui sont ainsi échangés entre ces cellules. Elles représentent donc un mode de communication intercellulaire majeur aussi bien en conditions physiologiques que pathologiques. C'est notamment le cas dans le système nerveux (SN) où les neurones et les cellules gliales forment un réseau très dense et où des milliards de connexions s'établissent. Cette revue fournit un aperçu des différents rôles joués par les VE dans un cerveau sain lors du renforcement des réseaux par exemple, mais également dans un cerveau malade où les VE participent, entre autres, à la progression des maladies neurodégénératives et tumorales.