Sex‐Dependent Effects of Gestational Intermittent Hypoxia Exposure in the 5XFAD Mouse Model of Alzheimer’s Disease

Abstract

The in utero environment is well known to influence CNS development and behavioral phenotypes, lasting well into adulthood. However, long‐term neurodevelopmental reprogramming is poorly understood in the context of sleep‐disordered breathing (SDB) during pregnancy despite its increased prevalence in recent years. Neurodegenerative diseases, including Alzheimer’s disease (AD), strongly correlate with the incidence of sleep apnea in humans, a manifestation of SDB. To address this, we utilized a genetic mouse model of Alzheimer’s disease (AD; hemizygous 5xFAD) after in utero exposure to gestational intermittent hypoxia (GIH), a hallmark of SDB during pregnancy. We tested the hypothesis that GIH exposure will exacerbate the neurodegeneration previously described in 5XFAD mice. Pregnant dams received intermittent hypoxia (90s alternating 6.5%/21% O2) or normoxia (90s alternating 21%/21% O2) for 12 hrs/day during their sleep cycle from gestational days 10‐18. At 4, 6, and 8 months of age, offspring were subjected to prefrontal cortex‐ and hippocampal‐dependent behavioral testing to assess disease‐related decline. Preliminary data show GIH‐dependent decline in 5XFAD male offspring and not females. After final behavioral testing, brains were harvested for immunohistochemistry analysis and immunomagnetic microglial isolation. Imaging analysis demonstrated cellular alterations including increased number of microglia and decreased number of astrocytes in 5XFAD females exposed to GIH, which was not seen in males. Studies are underway to analyze microglial immune responses, inflammatory and intercellular communication gene expression by RNA‐sequencing. Together, these data suggest that GIH may exacerbate neurocognitive decline and alter cellular responses to disease that correlates with altered microglial function, in a manner that differs by sex. These observations have implications for people with sleep apnea, particularly during pregnancy and the subsequent brain health of their offspring.