Identification of pathological pathways centered on circRNA dysregulation initiated at a critical window of Alzheimer’s disease progression

Although circRNA abnormalities are found in Alzheimer’s disease (AD) postmortem brains, whether and how altered circRNA landscape lead to pathological gene network changes during AD progression remain undefined. Employing our recently published experimental and computational approaches, we found genome-wide dysregulated circRNA expression and disrupted functional cooperation of circRNAs in sponging microRNAs (miRNAs) and RNA-binding proteins (RBPs) during early pathogenic progression in a mouse AD model. In addition, we identified AD progression-associated mouse circRNAs that are conserved and affected in AD patients, which underlie malfunction of downstream microRNAs and RBPs in AD brains. An exemplar circRNA is circGigyf2, which progressively declines along with AD pathogenic severity. Furthermore, we identified AD pathological pathways centered on circGigyf2, including upstream RBPs that control circGigyf2 biogenesis and downstream miRNA-mRNA and RBP-mRNA axis regulated by circGigyf2, all affected in AD patients. Our discoveries provide strong evidence suggesting the contribution of circRNA abnormality in early AD pathogenesis.