Male Mice Expressing Human APOE4 Genotype Exhibit Greater Baseline Respiratory Rate and Less Robust Hypoxic Ventilatory Response Than APOE3 Mice as Measured by Whole Body Plethysmography

Abstract

Breathing is vital for life and is both uniquely complex and vulnerable to disruption. Disorders of breathing such as those that occur in sleep apnea and even high cervical spinal cord injury (SCI) can impair quality of life and potentiate the ill effects of comorbidities like Alzheimer’s disease (AD). Indeed, studies have shown greater cognitive and cardiovascular impairments in subjects with sleep apnea and AD. Apolipoprotein E (ApoE) is a ubiquitous protein found throughout the body and CNS which aids in the regulation and transport of cholesterol and lipids. Moreover, the E4 allele confers a higher risk of early onset AD than either the E2 or E3 alleles. Previous research in our lab has shown the interaction between ApoE genotype and sex differentially affects breathing motor plasticity following SCI in mice. However, it is unknown how baseline respiratory pattern and capability during hypoxic challenge may differ between uninjured individuals expressing APOE4 and E3 alleles. Thus, with APOE genotype as our independent variable, we measured the respiratory parameters of male E3 and E4 targeted replacement mice using whole body plethysmography (WBP), hypothesizing that E3 animals would display a more adaptive, heightened response to hypoxic exposure than those expressing E4. Preliminary data comparing E3 animals (n=9) and E4 animals (n=8) demonstrated differences across several key measurements. At baseline, E4 animals were shown to breathe in an energy inefficient manner as exemplified high measures in tidal volume and frequency. During sustained hypoxia, frequency, tidal volume, and minute volume initially increased across all animals, but APOE3 animals mounted a much more robust and sustained response with APOE4 values falling well below baseline measures prior to termination of hypoxia. These preliminary results suggest a critical role of the APOE genotype in regulation of baseline breathing and in response to hypoxic conditions and that possessing the APOE4 allele may confer vulnerabilities in respiratory function and during environmental challenges leading to cognitive decline. Future directions include examining anatomically critical CNS respiratory regions and neural cell function.