Neuron-derived extracellular vesicles extracted from plasma show altered size and miRNA cargo as a function of antidepressant drug response

Abstract

Previous work has demonstrated that microRNAs (miRNAs) change as a function of antidepressant treatment (ADT) response. However, it is unclear how representative these peripherally detected miRNA changes are to those occurring in the brain. This study aimed to use peripherally extracted neuron-derived extracellular vesicles (NDEVs) to circumvent these limitations and investigate neuronal miRNA changes associated with antidepressant response. Samples were collected at two time points (baseline and after 8 weeks of follow-up) from depressed patients who responded (N=20) and did not respond (N=20) to escitalopram treatment, as well as controls (N=20). Total extracellular vesicles (EVs) were extracted from plasma, and then further enriched for NDEVs by immunoprecipitation with L1CAM. EV size was measured using tunable resistive pulse sensing, and NDEV miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Characterization of NDEVs revealed they were smaller than other EVs isolated from plasma (p<0.0001), had brain-specific neuronal markers, and contained miRNAs enriched for brain functions (p<0.0001) Furthermore, NDEVs from depressed patients were smaller than controls (p<0.05), and NDEV size increased with ADT response (p<0.01). Finally, changes in NDEV cargo, specifically changes in miR-21-5p, miR-30d-5p and miR-486-5p together (p<0.01), were associated with ADT response. Targets of these three miRNAs were altered in brain tissue from depressed individuals (p<0.05). Together, this study indicates that changes in peripherally isolated NDEVs can act as both a clinically accessible and informative biomarker of ADT response specifically through size and cargo.

Urinary Astrocyte-derived Extracellular Vesicles: A Non-invasive Tool for Capturing HumanIn VivoMolecular “Movies” of Brain

“…Theoretically, uTEVs may also contain EVs derived from other CNS cells, such as neurons and various types of glial cells, including microglia and oligodendrocytes, which could be isolated using similar methods. For other types of BDEVs, such as NDEVs, L1 cell adhesion molecule (L1CAM) is commonly used as a marker [55][56][57] . However, L1CAM expression is also detected in the kidney 58 , potentially compromising the purity of urinary L1CAM + EVs that are truly derived from CNS.…”

A new diagnostic tool for brain disorders: extracellular vesicles derived from neuron, astrocyte, and oligodendrocyte

“…One study targeted eight previously reported miRNAs associated with depression and identified stable detection of let-7a-5p, miR-34a-5p, miR-132-3p, miR-182-5p, miR-212-3p, and miR-1202 in NDEs (Mizohata et al, 2021). The other study was carried out on 75 miRNAs by microarray and found that changes in miR-21-5p, miR-30d-5p, and miR-486-5p were associated with antidepressant drug response (Saeedi et al, 2021).…”

“…Except that, most current studies of CNS-derived EVs only detected specific biomolecules of interest, and these results have yet to undergo validation by other research teams. A limited number of papers have used genome-wide approaches to investigate the expression pattern of CNS-derived EVs (Serpente et al, 2020;Zou et al, 2020;Anastasi et al, 2021;Arioz et al, 2021;Saeedi et al, 2021;Zhong et al, 2021). These studies have employed omics screening to predict disease status and have revealed new potential protein or miRNA biomarkers.…”

miR-218: A Stress-Responsive Epigenetic Modifier

“…This process can be taken a step further by isolating brain-derived exosomes from patient blood samples. These small, extracellular signaling vesicles released from neurons in the brain for communication can more accurately reflect the levels of expression present in the central nervous system [ 117 ]. In this way, we can explore the viability of miR-218 as a biomarker for depression.…”