Related Experiment Video
Updated: May 11, 2026
Generation of a Chronic Obstructive Pulmonary Disease Model in Mice by Repeated Ozone Exposure
Published on: August 25, 2017
Chronic intermittent hypoxia exposure induces a unique microglial transcriptome in 5XFAD mice
Kaitlyn M Marino1, Andrea C Ewald1, Jaidynne N Lash1
1University of Wisconsin-Madison.
Abstract:
Clinical observations suggest that obstructive sleep apnea (OSA) and Alzheimer's disease (AD) pathology may be linked; however, causal mechanisms and relationships are unclear. To investigate the potential interaction between amyloidosis and intermittent hypoxia (IH), a hallmark of OSA, starting at 4-months of age 5XFAD mice were exposed to chronic IH (CIH) consisting of 20 episodes per hour of hypoxia for 12 hours/day, daily for 4- (males) or 6-months (females). CIH did not induce significant changes in amyloid burden or the number of astrocytes in males or females, but there was a slight decrease in the number of microglia observed in the cortex of 5XFAD mice of both sexes. To further explore this effect, we performed bulk RNA sequencing on isolated microglia. In WT mice, the most robust gene changes induced by CIH were identified in male microglia, many of which were pro-inflammatory. In microglia from 5XFAD mice, compared to NX, CIH exposure induced comparatively more DEGs in males. Further, in genes that were upregulated by CIH in WT vs 5XFAD mice of both sexes, there was an enrichment of pathways associated with oxidative phosphorylation, aerobic and cellular respiration, and ATP synthesis. These changes indicate that CIH has a more robust effect on the microglial transcriptome in 5XFAD mice than in WT mice, suggesting that the synergy between AD and OSA pathologies may be driven by metabolic changes in the microglial transcriptome. These observations are particularly interesting given the known sex differences in OSA and AD pathology in human disease.
Insights
Obstructive sleep apnea (OSA) and Alzheimer's disease (AD) may interact through metabolic changes in microglia. Chronic intermittent hypoxia (CIH) robustly altered microglial gene expression in AD model mice, suggesting a link between these conditions.
Area of Science:
- Neuroscience
- Sleep Medicine
- Genomics
Background:
- Clinical observations suggest a link between obstructive sleep apnea (OSA) and Alzheimer's disease (AD).
- The causal mechanisms and specific interactions between amyloidosis and intermittent hypoxia (IH), a hallmark of OSA, remain unclear.
- Sex differences are known in both OSA and AD human pathology.
Purpose of the Study:
- To investigate the potential interaction between amyloidosis and chronic intermittent hypoxia (CIH) in a mouse model of Alzheimer's disease.
- To explore the effects of CIH on microglial gene expression in the context of AD pathology.
- To identify potential molecular mechanisms underlying the synergy between OSA and AD.
Main Methods:
- 5XFAD mice and wild-type (WT) littermates were exposed to chronic intermittent hypoxia (CIH) for 4-6 months.
- Amyloid burden, astrocyte, and microglia counts were assessed.
- Bulk RNA sequencing was performed on isolated microglia to analyze gene expression changes.
Main Results:
- CIH did not significantly alter amyloid burden or astrocyte numbers in 5XFAD mice but slightly decreased microglia counts.
- CIH induced more robust changes in the microglial transcriptome of 5XFAD mice compared to WT mice, particularly in males.
- Upregulated genes in response to CIH in 5XFAD mice were enriched for pathways related to cellular respiration and ATP synthesis.
Conclusions:
- CIH has a more pronounced effect on the microglial transcriptome in the 5XFAD mouse model than in WT mice.
- Metabolic changes in microglia may be a key factor driving the synergy between Alzheimer's disease and obstructive sleep apnea pathologies.
- These findings highlight potential sex-specific interactions and warrant further investigation into the role of microglial metabolism in neurodegenerative diseases associated with sleep disorders.
