Brain research bulletin · 2026
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.
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Liu Yue, Fu Ruoting, Ge Chuanhua, Long Zhimin, Wang Huai, He Guiqiong
Аннотация
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.
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.