New windows into the brain: Central nervous system-derived extracellular vesicles in blood

Abstract

Extracellular vesicles (EVs), including exosomes and (shedding) microvesicles, are released by nearly all cell types and carry a cargo of proteins and nucleic acids that varies by the cell of origin. They are thought to play critical roles in normal central nervous system (CNS) function and neurological disorders. A recently revealed key characteristic of EVs is that they may travel between the CNS and peripheral circulation. This property has led to intense interest in how EVs might serve as a vehicle for toxic protein clearance and as a readily accessible source of biomarkers for CNS disorders. Furthermore, by bypassing the blood-brain barrier, modified EVs could serve as a unique drug delivery system that targets specific neuronal populations. Further work is necessary to develop and optimize techniques that enable high-yield capture of relevant EV populations, analyze individual EVs and their cargos, and validate preliminary results of EV-derived biomarkers in independent cohorts.

Keywords: Alzheimer disease; Biomarker; Brain-periphery communication; CNS drug delivery; Exosome; Extracellular vesicle; Neurological disorder; Parkinson disease.

Figure 1,. Diagram of possible EV transport mechanisms from the central nervous system to peripheral blood.

A) Direct translocation of EVs into capillaries or draining venules via the BBB; B) EVs passing through interstitial fluid into the CSF and then the venous system via the arachnoid granulations; C) EVs are transported into the perinasal lymphatics, with or without passage through the CSF, and then into the venous system. BBB, blood-brain barrier; CSF, cerebrospinal fluid; EV, extracellular microvesicle.

Figure 2,. Potential clinical applications utilizing the bidirectional transfer of EVs between the brain and peripheral blood.

A) CNS EVs carrying disease-specific molecular signatures of CNS disorders can be transported from the brain to peripheral blood and isolated/analyzed based on CNS- or brain cell-specific surface markers. Their cargo of protein and nucleic acid is likely to reflect core pathogenic intracellular processes in their originating brain cells, and could serve as a novel biomarker source for CNS disorders. B) EVs carrying signal molecules can be transported via the BBB or other pathways from peripheral blood into the brain to target specific cell types. EVs, particularly those capable of transiting the BBB, may be modified to deliver therapeutic molecules in a variety of CNS conditions. BBB, blood-brain barrier; CNS, central nervous system; EV, extracellular microvesicle.