Havaki, S. | Search bioRxiv

bioRxiv2025

Human- and Rodent-derived Extracellular Vesicles Mediate the Spread of Pathology in MSA-like Models

Multiple system atrophy (MSA) is characterized by the presence of protein-rich inclusions mainly within oligodendrocytes, comprised primarily by the neuronal protein Synuclein and the oligodendroglial-specific phosphoprotein TPPP/p25. Mature oligodendrocytes do not normally express detectable Synuclein levels, suggesting that its oligodendroglial accumulation may arise from intercellular transfer, potentially via extracellular vesicles (EVs); however the precise role of oligodendroglial-derived EVs in MSA progression remains relatively understudied. Herein, we characterized the cargo/features and pathogenic potential of EVs released by oligodendrocytes treated with human Synuclein fibrils amplified from MSA or Parkinsons disease patient brains (or human recombinant Synuclein fibrils) and EVs isolated from murine and human MSA (or respective control) brains. Our findings reveal that both oligodendroglial cell- and brain-derived EVs harbor pathological Synuclein and TPPP/p25 conformations, similar to those accumulating in human MSA brains. These EVs are readily taken up by both neurons and oligodendrocytes, driving Synuclein propagation in vitro. Importantly, inoculation of these MSA-like EVs in animal models induce robust pSer129-Synuclein accumulation along the nigrostriatal axis, colocalizing with markers of mature oligodendrocytes and dopaminergic neurons. These findings underscore the pivotal role of oligodendroglial-derived EVs in pathology progression and neuronal-oligodendroglial communication, positioning them as promising targets for therapeutic strategies aimed at combating alpha-Synucleinopathies.

neuroscience↗

bioRxiv2023

Senescent cells in Giant Cell Arteritis have inflammatory phenotype participating in tissue injury via IL-6 dependent pathways

ObjectivesAge is the strongest risk factor of Giant Cell Arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multi-marker algorithm in tissue artery biopsies (TABs) of GCA patients. MethodsSeventy five positive TABs from GCA patients and 22 negative from patients with Polymyalgia Rheumatica (PMR) were retrospectively retrieved and analyzed. Senescent cells and their histologic origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype (SASP) by triple co-staining. GCA or PMR artery culture supernatants were applied to primary skin fibroblasts with or without IL-6 blocking agent to explore the induction of IL-6 associated cellular senescence. ResultsSenescent cells were mainly present in GCA arteries at higher proportion compared to PMR (9.50% vs 2.66% respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts and macrophages while MMP-9 by fibroblasts only. IL-6 positive senescent cells were associated with the extension of vascular inflammation (adventitial limited disease vs transmural inflammation: 10.02% vs 4.37% respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6 blockade. ConclusionsSenescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk. These findings might suggest a potential implication in disease pathogenesis by perpetuating inflammation and affecting vascular remodeling via IL-6 dependent mechanisms.

cell biology↗