Alterations of plasma neuron-derived exosomal microRNAs in patients with bipolar disorder

Abstract

MicroRNAs (miRNAs) alterations in patients with bipolar disorder (BD) are pivotal to the disease’s pathogenesis. Since obtaining brain tissue is challenging, most research has shifted to analyzing miRNAs in peripheral blood. One innovative solution is sequencing miRNAs in plasma exosomes, particularly those neuron-derived exosomal miRNAs emanating from the brain. In our study, we isolated plasma neuron-derived exosomes from 85 patients with BD and 39 healthy controls using biotinylated antibodies targeting a human neuronal marker. These exosomes were then subjected to miRNA sequencing and expression analysis. Out of the 2,656 neuron-derived exosome miRNAs identified, 14 were differentially expressed between BD patients and controls. This differential expression was consistent even when the sample was split into discovery and validation groups. Notably, the expression trend remained unchanged between patients in either the depressive or manic phase. Moreover, the target genes of hsa-miR-143-3p displayed distinct expression patterns in the prefrontal cortex of BD patients versus healthy controls, as sourced from PsychENCODE data. Through weighted gene co-expression network analysis, a module linking to clinical symptoms of BD patients was discerned. Enrichment analyses unveiled these miRNAs’ role in modulating the PI3K-AKT signaling pathway, axon guidance, and focal adhesion. To summarize, our findings provide the first evidence of dysregulated plasma neuron-derived exosome miRNAs in BD patients, further buttressing the neurogenic hypothesis of BD.