A circRNA ceRNA network involved in cognitive dysfunction after chronic cerebral hypoperfusion

Abstract

Chronic Cerebral Hypoperfusion (CCH) is associated with cognitive dysfunction, the underlying mechanisms of which remain elusive, hindering the development of effective therapeutic approaches. In this study, we employed an established CCH animal model to delve into neuropathological alterations like oxidative stress, inflammation, neurotransmitter synthesis deficits, and other morphological alterations. Our findings revealed that while the number of neurons remained unchanged, there was a significant reduction in neuronal fibers post-CCH, as evidenced by microtubule-associated protein 2 (MAP2) staining. Moreover, myelin basic protein (MBP) staining showed exacerbated demyelination of neuronal fibers. Furthermore, we observed increased neuroinflammation, proliferation, and activation of astrocytes and microglia, as well as synaptic loss and microglial-mediated synapse engulfment post-CCH. Utilizing RNA sequencing, differential expression analysis displayed alterations in both mRNAs and circRNAs. Following gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, both showed significant enrichment in immunological and inflammation-related terms and pathways. Importantly, the differentially expressed circular RNAs (DE circRNAs) exhibited a notable coexpression pattern with DE mRNAs. The ternary circRNA-miRNA-mRNA competing endogenous RNAs (ceRNA) network was constructed, and subsequent analysis reiterated the significance of neuroimmunological and neuroinflammatory dysfunction in CCH-induced neuropathological changes and cognitive dysfunction. This study underscores the potential role of circRNAs in these processes, suggesting them as promising therapeutic targets to mitigate the detrimental effects of CCH.