Multi-omics analysis identifies the miR-28a-5p/SerpinA3N/PI3K/AKT axis as a regulator of microglial neuroinflammation and cognitive decline in Alzheimer's disease
- Brain Res Bull. 2026 Sep:243:111994. doi: 10.1016/j.brainresbull.2026.111994.
- 1. Center for Neuroscience Research, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China; Department of Anatomy, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
- 2. Department of Neurosurgery, Tongren People's Hospital, Guizhou 554300, China.
- 3. Center for Neuroscience Research, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China; Department of Anatomy, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
- 4. Center for Neuroscience Research, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China; Department of Anatomy, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
Introduction: Neuroinflammation driven by microglial dysfunction is a central pathological feature of Alzheimer's disease (AD). However, the precise regulatory networks, particularly those involving post-transcriptional control by MicroRNAs (miRNAs), remain incompletely understood.
Methods: We performed integrated multi-omics analysis (miRNA-seq, mRNA-seq, TMT-based proteomics) on hippocampal tissues from APP/PS1 and wild-type mice. Functional validation was conducted in vitro using BV2 microglial cells and in vivo via stereotaxic injection of miR-28a-5p agomir in APP/PS1 mice, combined with molecular, inflammatory, and behavioral assessments.
Results: Multi-omics integration identified SerpinA3N as a core upregulated target in a high-confidence miRNA-mRNA-protein network, with good discriminative ability across AD mouse models. SerpinA3N promoted microglial M1 polarization, enhanced TNF-α/IL-1β/IL-6 secretion, and suppressed the M2 marker Arg1 by inhibiting the PI3K/Akt pathway. miR-28a-5p was identified as a direct upstream repressor of SerpinA3N, and its downregulation in AD models contributed to SerpinA3N upregulation. Rescue experiments confirmed SerpinA3N mediates miR-28a-5p's neuroinflammatory effects. In vivo, miR-28a-5p overexpression reduced SerpinA3N, restored PI3K/Akt activity, alleviated neuroinflammation, and improved learning/memory deficits in APP/PS1 mice.
Conclusion: Our study defines a novel miR-28a-5p/SerpinA3N/PI3K/Akt regulatory axis governing pro-inflammatory microglial activation and cognitive function in AD. SerpinA3N and miR-28a-5p show potential as preclinical research biomarkers in AD.