Whole-transcriptome sequencing reveals Alzheimer's disease-associated ceRNA regulatory networks and downstream pathways.

OBJECTIVE

Alzheimer's disease (AD) molecular mechanisms remain unclear, and effective therapies are lacking. This study employed whole-transcriptome sequencing to investigate the expression profiles of circRNAs, lncRNAs, miRNAs, and mRNAs in the hippocampus of APP/PS1 transgenic mice, aiming to identify ceRNA regulatory networks and clarify their roles in AD pathogenesis.

METHODS

Differentially expressed RNAs were integrated into ceRNA networks, and programmed cell death-related pathways were analyzed using GO and KEGG. The computationally predicted circRNA_13083/miR-298-5p/CD14 axis was preliminarily evaluated in vitro using siRNA-mediated CD14 knockdown in microglial and neuronal AD models. Expression of CD14, NF-κB components, and NLRP3 markers was measured by qRT-PCR, while secreted IL-1β and IL-18 protein levels were quantified via ELISA. Neuronal survival was assessed via CCK-8 assays.

RESULTS

Transcriptome analysis revealed 376 differentially expressed mRNAs, 491 lncRNAs, 5,253 circRNAs, and 21 miRNAs, which formed extensive ceRNA interaction networks. Functional enrichment highlighted programmed cell death pathways, including NF-κB and inflammasome signaling. The circRNA_13083/miR-298-5p/CD14 axis emerged as a key regulatory node. qRT-PCR confirmed elevated CD14 expression in AD models. CD14 knockdown significantly attenuated Aβ1-42-induced NF-κB activation, NLRP3 inflammasome assembly, and proinflammatory cytokine release. Conditioned medium transfer experiments further demonstrated that CD14 silencing alleviated microglia-mediated neuronal damage and improved HT-22 cell survival.

CONCLUSION

Whole-transcriptome sequencing uncovered extensive ceRNA regulatory networks in AD hippocampus, with the circRNA_13083/miR-298-5p/CD14 axis potentially implicated in neuroinflammation and programmed cell death through NF-κB signaling. Silencing CD14 mitigates microglial activation and neuronal injury, highlighting its potential as a therapeutic target for AD.