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Background <p>Obstructive 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.</p> Methods <p>Mice 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.</p> Results <p>CIH-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.</p> Conclusion <p>Through 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.</p> Graphical abstract <p>The alveolar epithelial cells of patients with chronic intermittent hypoxia secrete a large number of miR-106a-5p EVs through the lung brain axis, which act on brain tissue, leading to increased polarization of microglia M1 and neuronal cell apoptosis.</p> <p></p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Bailun Wang,
  • Chang Sun,
  • Ruiqiu Zhang,
  • Angran Gu,
  • Manman Zhao,
  • Xiaobing Zhou,
  • Changping Gu

摘要

Background

Obstructive 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.

Methods

Mice 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.

Results

CIH-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.

Conclusion

Through 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.

Graphical abstract

The alveolar epithelial cells of patients with chronic intermittent hypoxia secrete a large number of miR-106a-5p EVs through the lung brain axis, which act on brain tissue, leading to increased polarization of microglia M1 and neuronal cell apoptosis.