Extracellular vesicles (EVs) released by neurons (nEVs) provide an opportunity to measure biomarkers from the brain circulating in the periphery. No study yet has directly compared molecular cargo in brain tissue to nEVs found in circulation in humans. We compared the levels microRNAs and environmental chemicals because microRNAs are one of the most studied nEV cargoes and offer great potential as biomarkers and environmental chemical load in nEVs is understudied and could reveal levels of chemicals in the brain. To do so, we leveraged matched sets of brain tissue and serum, and isolated serum total EVs and serum nEVs. We also generated and compared metabolomic profiles in a different set of matched serum, serum total EVs, and serum nEVs since metabolite cargo in nEVs is also understudied but could offer potential biomarkers. Highly expressed brain tissue miRNAs showed stronger correlations with nEVs than serum or total EVs. We detected several environmental chemical pollutant classes in nEVs. The chemical pollutant concentrations in nEVs were more strongly correlated with brain tissue levels than those observed between brain tissue and serum or total EVs. We also detected several endogenous metabolite classes in nEVs. Compared to serum and total EVs, there was enrichment of metabolites with known signaling roles, such as bile acids, oleic acid, phosphatidylserine, and isoprenoids. We provide evidence that nEV cargo is closely correlated to brain tissue content, further supporting their utility as a brain liquid biopsy.

Dr. Eitan and Dr. Volpert work and hold stocks in NeuroDex, a for-profit organization.

V.K. was supported by NIH/NIA grant P20AG093975. H.W. and A.A.B. were supported by NIH/NIEHS grant R35ES031688.

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IRB of Columbia University Irving Medical Center gave ethical approval for this work.

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