Whole-Transcriptome Analysis of APP/PS1 Mouse Brain and Identification of circRNA-miRNA-mRNA Networks to Investigate AD Pathogenesis

Alzheimer's disease (AD) is one of the most common forms of dementia and is characterized by a progressive loss of cognition. A hallmark of AD is known to be the extensive distribution of neuronal tangles and amyloid plaques in the brain, but the molecular and cellular complexity of AD remains poorly elucidated, which limits the development of effective clinical treatments for AD. Accumulating evidence indicates that noncoding RNAs participate in AD-associated pathophysiology, but the details are largely unknown. Moreover, although recent studies have revealed a potential link between AD and circular RNA (circRNA)-associated competing endogenous RNA (ceRNA) networks, few genome-wide studies have identified putative circRNA-associated ceRNA pairs involved in AD. Here, we used deep RNA sequencing to systematically investigate circRNA-associated ceRNA mechanisms in the brain of AD model mice (APP/PS1). Our results identified 235, 30, and 1,202 significantly dysregulated circRNAs, microRNAs (miRNAs), and mRNAs, respectively, and we used the sequencing data to construct the most comprehensive circRNA-associated ceRNA networks to date in the APP/PS1 brain. Gene Ontology (GO) analysis revealed that the identified networks are involved in regulating AD development from distinct origins, such as from the dendrite (GO: 0030425) and the synapse (GO: 0045202). Following rigorous selection, the circRNA-associated ceRNA networks in this AD mouse model were discovered to be mainly involved in dendritic development and memory (Sorbs2) and mouse neural development (ALS2). This study presents the first systematic dissection of circRNA-associated ceRNA profiles in the APP/PS1 mouse brain, and the identified circRNA-associated ceRNA networks could provide insights that facilitate AD diagnosis and therapy in the future.