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Objective <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p>

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Whole-transcriptome sequencing reveals Alzheimer’s disease–associated ceRNA regulatory networks and downstream pathways

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月27日

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  • KeFei Duan,
  • Fangfang Zhan,
  • Yaodan Zhang,
  • Xinghang Wang,
  • Gaoteng Lin,
  • Xiaoyi Zhao,
  • Dan Yu,
  • Shida Duan,
  • Yuan Ma

摘要

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.