Microglia as modulators of exosomal alpha-synuclein transmission

Abstract

Recent researches regarding to exosomal involvement in alpha-synuclein (α-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 α-syn-associated exosomes and the underlying mechanism of exosomes-involved communication in the synucleinopathy pathogenesis. To determine the contribution of α-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 α-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 α-syn to neurons. The release of human exosomal α-syn from microglia may facilitate this propagation. Finally, we described a mechanism underlying this potential role of microglia in the transmission of exosomal α-syn. Specifically, exogenous exosomes were found to dysregulate autophagy of the BV2 mouse microglia cell line with presentation of increased accumulation of intracellular α-syn and accelerated secretion of α-syn into extracellular space. These results suggest that microglia play a crucial role in the transmission of α-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.

Intrastriatal Administration of Exosome-Associated Pathological Alpha-Synuclein Is Not Sufficient by Itself to Cause Pathology Transmission

“…***p < 0.001. secreted vesicle-associated α-syn appears to be internalized by primary neurons. This is in agreement with data of Xia et al, who also observed that exogenous exosomes are taken up by neuronal and microglia cells, both in vitro and in vivo (Xia et al, 2019). Moreover, human α-syn has been shown to accumulate in neuronal cells following hippocampal injection of exosomes derived from patients with dementia with LBs (DLB) (Ngolab et al, 2017).…”

“…Together, our results, using exosomes as carrier vesicles of pathological α-syn, indicate that exosomes alone are insufficient to induce robust LB-like pathology in wt mouse brains. We should note here that irrespective of the pathogenic potential of their α-syn cargo, we and others have noticed that exosomes are taken up less efficiently from neurons than other cell types, like microglia (Xia et al, 2019). This limited access might also affect their potential to recruit the endogenous neuronal α-syn and transmit pathology in vivo.…”

“…Moreover, Xia et al (2019) demonstrated transmission of pathology in the mouse brain following injection of plasma exosomes derived from PD patients. Although not neuronal in origin, the plasma exosomes isolated from PD patients may contain the α-syn species necessary for the templating and seeding of the endogenous α-syn.…”

“…In vivo, administration of PD patient plasma-derived exosomes barely colocalize with neuronal cells in contrast to their strong preference for microglia cells near the injection site. Nonetheless, human α-syn was detected in the Substantia Nigra pars compacta (SNpc) neurons, which implies a glia-neuron transmission process as well (Xia et al, 2019).…”

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

“…Exosomes are produced and released by virtually all cell types, including different brain cells, such as neurons, astrocytes, microglia, and oligodendrocytes (Potolicchio et al, 2005;Fauré et al, 2006;Krämer-Albers et al, 2007;Bianco et al, 2009;Dutta et al, 2018;Goetzl et al, 2018;Xia et al, 2019). The nomenclature used in the field is somewhat problematic.…”