Reactive microglia enhance the transmission of exosomal alpha-synuclein via toll-like receptor 2.

Increasing evidence suggests that microglial activation is strongly linked to the initiation and progression of Parkinson's disease (PD). Cell-to-cell propagation of α-synuclein (α-syn) pathology is a highlighted feature of PD, and the focus of such research has been primarily on neurons. However, recent studies as well as the data contained herein suggest that microglia, the primary phagocytes in the brain, play a direct role in the spread of α-syn pathology. Recent data revealed that plasma exosomes derived from PD patients (PD-EXO) carry pathological α-syn and target microglia preferentially. Hence, PD-EXO is likely a key tool for investigating the role of microglia in α-syn transmission. We showed that intrastriatal injection of PD-EXO resulted in the propagation of exosomal α-syn from microglia to neurons following microglia activation. Toll-like receptor 2 (TLR2) in microglia was activated by exosomal α-syn and acted as a crucial mediator of PD-EXO-induced microglial activation. Additionally, partial microglia depletion resulted in a significant decrease of exogenous α-syn in the substantia nigra (SN). Furthermore, exosomal α-syn internalization was initiated by binding to TLR2 of microglia. Excessive α-syn phagocytosis may induce the inflammatory responses of microglia and provide the seed for microglia-to-neuron transmission. Consistently, TLR2 silencing in microglia mitigated α-syn pathology in vivo. Overall, the present data support the idea that the interaction of exosomal α-syn and microglial TLR2 contribute to excessive α-syn phagocytosis and microglial activation, which lead to the further propagation and spread of α-syn pathology, thereby highlighting the pivotal roles of reactive microglia in α-syn transmission.