Dynamics and role of covalently-closed circular RNAs in Alzheimer's disease: A review of experimental and bioinformatics studies

Alzheimer's disease (AD) is an age-associated disorder characterized by cognitive decline, with dementia representing the final stage of a complex clinical-biological process rather than simply a more severe form of cognitive decline. Circular RNAs (circRNAs), novel non-coding RNAs, have emerged as key regulators of brain function and associated disorders. This study explores the role of circRNAs in AD by reviewing experimentally validated circRNAs in human and animal models. We identified 10 human (seven pathogenic, three protective) and six animal (three pathogenic, three protective) AD-related circRNAs. Experimental studies have confirmed that human protective circRNAs are predominantly downregulated in AD, where they function by sequestering specific miRNAs within cells, particularly miR-7, miR-142–5p, and miR-217, which have well-recognized neuroinflammatory functions. In-silico analysis revealed that circLPAR1 (pathogenic), circHUWE1 (pathogenic), and circHOMER1 (protective) interact with miRNAs that mainly control AD-related genes. Notably, circHOMER1 plays a key role in regulating multiple AD-related pathways, including autophagy, apoptosis, and PI3K-AKT and amyloid fiber formation. Furthermore, circRNA/protein interaction analysis revealed that circHUWE1 predominantly associates with RNA transport proteins, whereas circHOMER1 interacts with proteins involved in mRNA surveillance pathways. Remarkably, docking analysis demonstrated that circAβ-a (pathogenic) exhibits a strong affinity for eukaryotic translation initiation factor 4A3 protein, while circHOMER1 shows a higher binding affinity for DGCR8 microprocessor complex subunit protein. Our study presents a concise list of circRNAs as potential key targets for further investigation in AD research. Future experimental research is essential to uncover their precise mechanisms and assess their potential as biomarkers, offering promising avenues for developing interventions to alleviate cognitive decline in AD. • 10 human circRNAs have been experimentally confirmed in Alzheimer's disease (AD). • circ-LPAR1 interacts with a higher number (over 30) of AD-related miRNAs. • circ-LPAR1, -HUWE1, and -HOMER1 miRNA interactions regulate AD-related pathways. • ELAVL1, FMR1, and AGO2 are top-hub proteins interacting with AD-related circRNAs. • circAβ-α and -HOMER1 have higher affinity to EIF4A3 and DGCR8 proteins respectively.