Multi-layered transcriptomic analysis reveals a pivotal role of FMR1 and other developmental genes in Alzheimer's disease-associated brain ceRNA network

Alzheimer's disease (AD) is an increasingly neurodegenerative disorder that causes progressive cognitive decline and memory impairment. Despite extensive research, the underlying causes of late-onset AD (LOAD) are still in progress. This study aimed to establish a network of competing regulatory interactions involving circular RNAs (circRNAs), microRNAs (miRNAs), RNA-binding proteins (RBPs), and messenger RNAs (mRNAs) connected to LOAD. A systematic analysis of publicly available expression data was conducted to identify integrated differentially expressed genes (DEGs) from the hippocampus of LOAD patients. Subsequently, gene co-expression analysis identified modules comprising highly expressed DEGs that act cooperatively. The competition between co-expressed DEGs and miRNAs/RBPs and the simultaneous interactions between circRNA and miRNA/RBP revealed a complex ceRNA network responsible for post-transcriptional regulation in LOAD. Hippocampal expression data for miRNAs, circRNAs, and RBPs were used to filter relevant relationships for AD. An integrated topological score was used to identify the highly connected hub gene, from which a brain core ceRNA subnetwork was generated. The Fragile X Messenger Ribonucleoprotein 1 (FMR1) coding for the RBP FMRP emerged as the prominent driver gene in this subnetwork. FMRP has been previously related to AD but not in a ceRNA network context. Also, the substantial number of neurodevelopmental genes in the ceRNA subnetwork and their related biological pathways strengthen that AD shares common pathological mechanisms with developmental conditions. Our results enhance the current knowledge about the convergent ceRNA regulatory pathways underlying AD and provide potential targets for identifying early biomarkers and developing novel therapeutic interventions.