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

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