Respiratory Control in a Rat Model of Alzheimer's Disease (TgF344‐AD)

Abstract

Synaptic defects seen in tauopathies such as Alzheimer's disease (AD) are known to result in the impaired function of major brain networks. It is plausible to consider that such changes can directly or indirectly affect central respiratory networks within the brainstem with consequences for respiratory homeostasis. Alzheimer's patients display indicative signs of oro‐pharyngeal complications and sleep‐disordered breathing. Upper airway dysfunction has also been shown to develop and persist in animal models of AD. The aim of this study was to characterise respiratory control at an early stage of disease progression in a novel rat model of AD.We utilised a transgenic (Tg) rat model of AD (TgF344‐AD), which expresses the mutant human transgenes: amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9). Tg (male n=9; female n=12) and non‐transgenic wild type (non‐Tg; male n=8; female n=7) animals (34–49 weeks) were studied using whole‐body plethysmography to determine ventilation and metabolism. Cardiorespiratory reflex responses to chemostimulation were subsequently determined in a subset of animals under urethane anaesthesia (1.5g/kg). Data were statistically compared by 2‐way ANOVA (genotype × sex) with Bonferroni post hoc tests.Transgenic mutation did not significantly alter baseline minute ventilation (VE; p>0.05) however, sex‐specific differences in breathing were evident. Exposure to 10 minutes of hypoxia (FiO2 =0.1) manifested a greater VE response in females compared with males (p<0.01); however, the ventilatory response to hypoxia was equivalent in Tg animals compared with non‐Tg animals. Similarly, baseline data recorded under anaesthesia revealed that VE was equivalent in Tg and non‐Tg animals (p>0.05) and consistent with data derived from plethysmography, sex differences in breathing were evident. No genotype or sex difference was observed in diaphragm integrated EMG activity for peak amplitude, area under the curve and maximum slope analysis (p>0.05). Baseline mean arterial pressure (MAP) was equivalent in Tg and non‐Tg animals (p>0.05), although females had a significantly increased MAP compared with males (p<0.01).In conclusion, expression of human transgenes in this AD animal model did not significantly alter respiratory behaviour. Further analysis of respiratory stability and respiratory EMG responses to chemostimulation and airway obstruction will be carried out.Support or Funding InformationDepartment of Physiology, University College Cork, Cork, Ireland