Transmission of α-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson's disease?

Parkinson's disease (PD) pathophysiology develops in part from the formation, transmission, and aggregation of toxic species of the protein alpha-synuclein (alpha-syn). Recent evidence suggests that extracellular vesicles (EVs) may play a vital role in the transport of toxic alpha-syn between brain regions. Moreover, increasing evidence has highlighted the participation of peripheral molecules, particularly inflammatory species, which may influence or exacerbate the development of PD-related changes to the central nervous system (CNS), although detailed characterization of these species remains to be completed. Despite these findings, little attention has been devoted to erythrocytes, which contain alpha-syn concentrations similar to 1000-fold higher than the cerebrospinal fluid, as a source of potentially pathogenic alpha-syn. Here, we demonstrate that erythrocytes produce alpha-syn-rich EVs, which can cross the BBB, particularly under inflammatory conditions provoked by peripheral administration of lipopolysaccharide. This transport likely occurs via adsorptive-mediated transcytosis, with EVs that transit the BBB co-localizing with brain microglia. Examination of microglial reactivity upon exposure to alpha-syn-containing erythrocyte EVs in vitro and in vivo revealed that uptake provoked an increase in microglial inflammatory responses. EVs derived from the erythrocytes of PD patients elicited stronger responses than did those of control subjects, suggesting that inherent characteristics of EVs arising in the periphery might contribute to, or even initiate, CNS alpha-syn-related pathology. These results provide new insight into the mechanisms by which the brain and periphery communicate throughout the process of synucleinopathy pathogenesis.