Obstructive sleep apnea syndrome (OSAS) is characterized by cycles of decreased blood oxygen saturation followed by reoxygenation due to transient apnea. Cognitive dysfunction is a complication of OSAS, but its mechanisms remain unclear. Eight-week-old C57BL/6J mice were exposed to intermittent hypoxia (IH) to model OSAS, and cognitive function and hippocampal gene expression were analyzed. Three groups were maintained for 28 days: an IH group (oxygen alternating between 10 and 21% in 2 min cycles, 8 h/day), sustained hypoxia group (SH) (10% oxygen, 8 h/day), and control group (21% oxygen). Behavioral tests and RNA sequencing (RNA-seq) analysis were performed. While Y-maze test results showed no differences, the IH group demonstrated impaired memory and learning in passive avoidance tests compared to control and SH groups. RNA-seq revealed coordinated suppression of mitochondrial function genes and oxidative stress response pathways, specifically in the IH group. RT-qPCR showed decreased Lars2, Hmcn1, and Vstm2l expression in the IH group. Pathway analysis showed the suppression of the KEAP1-NFE2L2 antioxidant pathway in the IH group vs. the SH group. Our findings demonstrate that IH induces cognitive dysfunction through suppression of the KEAP1-NFE2L2 antioxidant pathway and downregulation of mitochondrial genes (Lars2, Vstm2l), leading to oxidative stress and mitochondrial dysfunction. These findings advance our understanding of the molecular basis underlying OSAS-related cognitive impairment.
Miyo et al. (Sun,) studied this question.