Extracellular vesicles derived from monomeric -synuclein-treated microglia ameliorate neuroinflammation by delivery of miRNAs targeting PRAK

Parkinson's disease (PD) is characterized by the formation of Lewy body, which mainly contains misfolded alpha-synuclein. Microglial activation plays a role in neurodegeneration. The pathologically oligomeric alpha-synuclein promotes inflammatory microglia, while physiologically monomeric alpha-synuclein induces anti-inflammatory microglia, the relationship between these two forms in activating microglia and the molecular mechanism is essentially unknown. In this study, using in vivo and in vitro models, we challenged primary or BV2 microglia with exogenous stimuli including alpha-synuclein. We examined microglial activation and the underlying mechanism by Western blot, RT-PCR, ELISA, IF, FCM, miRNA sequencing and bioinformatic analysis. Oligomeric alpha-synuclein activated microglia via the involvement of the PRAK/MK5 pathway. The specific PRAK inhibitor GLPG0259 could mitigate microglial activation insulted by oligomeric alpha-synuclein. Monomeric alpha-synuclein regulated the anti-inflammatory microglia by delivering microglia-derived extracellular vesicles (EVs) in vitro and in vivo. Further sequencing and bioinformatic analysis of microglial EVs-associated miRNAs indicated that most of these miRNAs targeted PRAK. These results suggest that PRAK serves as an intersection in microglial activation when challenged with conformationally different alpha-synuclein. EVs derived from microglia treated with monomeric alpha-synuclein promote anti-inflammatory microglia by delivering miRNAs that target PRAK into recipient microglia.