Chronic intermittent hypoxia exposure induces a unique microglial transcriptome in 5XFAD mice

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.