LAUSR

Alzheimer’s disease (AD) is a neurodegenerative disease commonly associated with aging. Along with a decline in cognition and memory, individuals with AD often have respiratory disturbances such as sleep apnea, insufficient ventilation during sleep, and shortness of breath. Mechanisms underlying respiratory dysfunction in AD are unknown but may involve chemosensory deficits since at least one chemosensitive region, the locus coeruleus, undergoes significant neurodegeneration during AD progression in humans. To test the hypothesis that chemoreflexes are impaired in a mouse model of AD, we measured the hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses using whole body plethysmography in 5XFAD mice as amyloid pathology progressed. We evaluated 2 timepoints of amyloid beta (Aß) pathology: early (4 months of age) and late (8 months of age). Compared to WT mice, 8-month-old male and female 5XFAD mice had a significantly reduced capacity to increase ventilation following challenge with 5% inspired CO2 (males: 5XFAD 99 ± 11% vs WT 168 ± 18%; females: 5XFAD 126 ± 12% vs. WT 212 ± 12%) or 5% inspired O2 (males: 5XFAD 141 ± 20% vs. WT 201 ± 20%; females: 5XFAD 75 ± 7.6% vs. WT 134 ± 12%). In addition, both male and female 5XFAD mice experienced significantly more apneic events (~120 apneas per/h) than their WT counterparts (~50 apneas/h) during presumptive sleep. Consistent with impaired ventilation, Aß plaques were abundant in medullary regions of the brainstem where both central chemosensors and rhythm generating neurons reside. Preliminary data suggest that chemoreflex dysfunction may emerge early in disease progression since a trend toward a reduced HCVR (5XFAD 133 ± 23% vs WT 206 ± 39%, combined sexes) was apparent in 4-month-old 5XFAD mice. Surprisingly, and contrary to findings at 8 months, preliminary data in 4-month-old 5XFAD mice indicate that the HVR may be slightly higher indicating that 5XFAD mice may be hypersensitive to hypoxia early in disease progression. Together, these data suggest that responses to ventilatory challenges become significantly disrupted by Aß pathology late in disease progression, deficits which may manifest early in disease and could promote disease progression. Results from our studies will identify the contributions of Aß deposition to respiratory dysfunction in 5XFAD mice, and may have implications for therapeutic interventions in individuals with AD. NIH R01 HL142752, HL142752S1, and T32 AG000213 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.