Humanized ApoE4 Female Mice Exhibit a More Robust Hypoxic Ventilatory Response Than Female E3 Mice

Abstract

Breathing is essential to life and can be easily disrupted by many adverse events. Disorders such as high cervical spinal cord injury (SCI) and sleep apnea can decrease quality of life and enhance the ill effects of comorbidities like Alzheimer’s disease (AD). Previous studies have shown an increase in cognitive impairments in subjects with both sleep apnea and AD. Apolipoprotein E (ApoE) is a protein found throughout the body and central nervous system (CNS) that is involved in the regulation and transport of cholesterol and lipids. Out of the three APOE human alleles (E2, E3, and E4), the E4 allele has been implicated in the early onset and higher risk of AD when compared to E2 or E3. Previous research in our lab has shown that the interaction between APOE genotype and sex has different effects on breathing motor plasticity following a cervical SCI in mice. However, it is unknown how baseline respiratory pattern and capability differs between uninjured individuals expressing either ApoE4 or E3, specifically under hypoxic conditions. Unpublished data from our lab has examined these differences in male mice, showing that E4 male mice have high variation in respiratory pattern, as well as a less robust response to hypoxia. Using ApoE as our independent variable, we measured respiratory parameters of female C57/BL6 ApoE3 and ApoE4 humanized mice using whole body plethysmography (WBP), hypothesizing that ApoE3 animals would display a greater baseline respiratory rate and have a more adaptive, heightened response to hypoxic exposure than those expressing ApoE4. Preliminary data comparing E3 female animals (n=8) and E4 female animals (n=8) showed differences across several key measurements. Interestingly, ApoE4 humanized female mice had a more robust response to hypoxic exposure that failed to persist following cessation of hypoxia. However, at baseline, E4 female animals showed no differences in respiratory pattern in contrast to our previously collected male ApoE4 data. These results indicate a critical role of the APOE genotype in the regulation of breathing and response to hypoxic conditions which differs between males and females. To further understand this distinction, future experiments will examine differences in levels of brainstem and spinal cord serotonin expression between ApoE3 and E4 males and females, as well as plasticity following injury in areas high in ApoE expression.