ArticleJournal of neuroinflammation2025
MiR-106a-5p in extracellular vesicles derived from alveolar epithelial cells mediates cognitive dysfunction induced by chronic intermittent hypoxia in mice through MAPK signaling pathway.
Article in Journal of neuroinflammation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Nr1d1 Mediates Microglial Inflammatory Activation Induced by Intermittent Hypoxia: A Transcriptomic and Machine Learning Study.Journal of molecular neuroscience : MN · 2026Article
- Neuropsychiatric disorders in pulmonary fibrosis: from brain network alterations to inflammatory mechanisms and therapeutic implications.Journal of neuroinflammation · 2026Review
- Sedation as an Immunomodulator of Inflammatory Responses in the Lung-Brain Axis of ARDS.International journal of molecular sciences · 2026Review
- Obstructive sleep apnea as a modifier of endocrine toxicities associated with immune checkpoint inhibitors in lung cancer.Frontiers in immunology · 2026Review
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7 authors.
Funding
Abstract
backgroundObstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is frequently associated with cognitive dysfunction. However, the underlying peripheral-central interplay mechanism remains to be elucidated. Recent years have witnessed the proposal of the “lung-brain axis (LBA)” concept, suggesting that lung tissue can remotely regulate brain function via extracellular vesicles (EVs). This investigation aims to determine whether EVs derived from alveolar epithelial cells (AEC-EVs) mediate CIH-induced cognitive impairment and to delineate the associated molecular mechanisms.
methodsMice were exposed to CIH to model obstructive sleep apnea. EVs were isolated from brain tissue and MLE-12 cells via ultracentrifugation. CIH-AEC-EVs were administered to normal mice via tail vein injection; cognitive function was assessed using behavioral tests (Open Field, Y-Maze, Novel Object Recognition). In vitro, BV-2 cells were treated with CIH-AEC-EVs, and their polarization status was evaluated by Flow Cytometry (FCM), Quantitative Real-Time PCR (qPCR), Western Blotting (WB), and Immunofluorescence (IF). Key miRNAs and their target genes were screened and validated using miRNA sequencing, bioinformatics analysis, and dual-luciferase reporter assays. Finally, functional rescue experiments were performed using a miR-106a-5p inhibitor and a MAPK inhibitor to validate the functional outcomes both in vivo and in vitro.
resultsCIH-exposed mice exhibited cognitive impairment, hippocampal neuronal apoptosis, and increased M1 polarization of microglia. CIH markedly increased the abundance of alveolar-epithelial-cell-derived EVs (AEC-EVs) and microglial EVs in the brain, whereas neuron-derived EVs remained unchanged. CIH-AEC-EVs traversed the blood-brain barrier (BBB), were taken up by microglia, and induced M1 polarization while suppressing M2 polarization. Mechanistically, miR-106a-5p were enriched in CIH-AEC-EVs, which directly targeted DUSP2 mRNA, thereby relieving DUSP2-mediated suppression of ERK/MAPK signaling and facilitating M1 polarization. Administration of a miR-106a-5p antagonist or a MAPK inhibitor significantly reversed the aforementioned pathological alterations and ameliorated cognitive function.
conclusionThrough the lung-brain axis, CIH enhances the transfer of miR-106a-5p-loaded AEC-EVs to the hippocampus, where they downregulate DUSP2 and activate the MAPK signaling pathway. This alteration results in an M1/M2 microglial imbalance, which contributes to cognitive dysfunction. Targeted suppression of AEC-EVs secretion or the miR-106a-5p/DUSP2 axis may provide a potential non-invasive therapeutic strategy for addressing cognitive impairments associated with OSA.
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