Abnormal hypoxic and hypercapnic ventilatory responses in 5XFAD Alzheimer’s disease mice

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease commonly associated with aging. Along with regression in cognition and memory, AD patients often have respiratory disturbances such as sleep apnea, insufficient ventilation during sleep, and shortness of breath. Further, at least one chemosensitive region located in the pons, the locus coeruleus, undergoes dramatic degeneration during AD progression. These observations suggest chemoreception may be altered during the progression of AD. To begin testing this hypothesis, we examined the hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses on 5XFAD mice (>6months) using whole body plethysmography. Preliminary data showed a reduced capacity to lower metabolic rate and body temperature during hypoxia (5.5% inspired O2) in 5XFAD mice, such that average oxygen consumption was reduced by 34.8 ± 2.8% (S.E.M) and body temperature fell to 33.5 ± 0.4°C. In wild type (WT) mice oxygen consumption was reduced by 53% and body temperature fell to 32.8°C. Further, 5XFAD mice sustained a slight ventilatory increase (1.3 ± 3.6% increase from baseline) during hypoxia while WT mice reduced ventilation by 5%. 5XFAD mice also displayed a reduced hypercapnic ventilatory response, showing little increase in tidal volume in response to hypercapnia; but they appeared to augment this with a greater increase in breathing frequency compared to WT mice. The net result, however, was an increase in ventilation by 122 ± 22% from baseline in response to 5% CO2 while WT mice had a 181 ± 26% increase from baseline to the same challenge. Our data suggest that ventilatory chemoresponses are altered by disease progression in the 5XFAD mouse model. These alterations may contribute to the respiratory disturbances observed in AD patients.