Microglia as modulators of exosomal alpha-synuclein transmission

Recent researches regarding to exosomal involvement in alpha-synuclein (alpha-syn) transmission relating to the pathological process of Parkinson's disease (PD) have attracted considerable attention. It is highly desirable to make clear the diffusion process and cellular uptake of alpha-syn-associated exosomes and the underlying mechanism of exosomes-involved communication in the synucleinopathy pathogenesis. To determine the contribution of alpha-syn-associated exosomes to the initiation and progression of PD, plasma exosomes derived from PD patients were stereotaxically injected into the striatum of mice brains. Exosomes extracted from plasma diagnosed with PD contained monomeric and oligomeric alpha-syn. Here, we found that microglia display a high potency for uptake of plasma exosomes derived from PD patients, and therefore could be activated by exogenous exosomes in vitro and in vivo. In addition, immunofluorescent double staining verified the transfer of exogenous human exosomal alpha-syn to neurons. The release of human exosomal alpha-syn from microglia may facilitate this propagation. Finally, we described a mechanism underlying this potential role of microglia in the transmission of exosomal alpha-syn. Specifically, exogenous exosomes were found to dysregulate autophagy of the BV2 mouse microglia cell line with presentation of increased accumulation of intracellular alpha-syn and accelerated secretion of alpha-syn into extracellular space. These results suggest that microglia play a crucial role in the transmission of alpha-syn via exosomal pathways, in additional to idea that the progression of PD may be altered by the modulation of exosome secretion and/or microglial states.