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Chronic Intermittent Hypoxia Exposure Induces a Unique Microglial Transcriptome in 5XFAD Mice
Kaitlyn M Marino1,2, Andrea C Ewald3, Jaidynne N Lash2,3
1Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA.
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 h/day, daily for 4 months (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 normoxia (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. Chronic intermittent hypoxia (CIH) robustly altered microglial gene expression in AD mice, suggesting metabolic changes drive this synergy.
Area of Science:
- Neuroscience
- Pathology
- Genomics
Background:
- Clinical observations link obstructive sleep apnea (OSA) and Alzheimer's disease (AD).
- Causal mechanisms between amyloidosis and intermittent hypoxia (IH), a hallmark of OSA, remain unclear.
- Investigating the interplay between OSA and AD is crucial for understanding neurodegenerative disease progression.
Purpose of the Study:
- To investigate the potential interaction between amyloidosis and chronic intermittent hypoxia (CIH) in a mouse model of AD.
- 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, a model for AD, were exposed to chronic intermittent hypoxia (CIH) or normoxia (NX).
- 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.
- A slight decrease in microglia was observed in the cortex of CIH-exposed 5XFAD mice.
- CIH induced more significant gene expression changes in microglia from 5XFAD mice compared to wild-type (WT) mice, particularly in males.
- Upregulated genes in CIH-exposed 5XFAD mice were enriched in pathways related to cellular respiration and ATP synthesis.
Conclusions:
- CIH has a more pronounced effect on the microglial transcriptome in 5XFAD mice than in WT mice.
- Metabolic changes in microglial gene expression may underlie the synergistic effects of OSA and AD pathologies.
- Sex differences in response to CIH were observed, mirroring human disease patterns.
