Blunted Respiratory Responses in the Streptozotocin-Induced Alzheimer's Disease Rat Model

Alzheimer's disease (AD) is known for the progressive decline of cognition and memory. In addition to these disease-defining symptoms, impairment of respiratory function is frequently observed and often expressed by sleep-disordered breathing or reduced ability to adjust respiration when oxygen demand is elevated. The mechanisms for this are widely unknown. Postmortem analysis from the brainstem of AD patients reveals pathological alterations, including in nuclei responsible for respiratory control. In this study, we analyzed respiratory responses and morphological changes in brainstem nuclei following intracerebroventricular (ICV) injections of streptozotocin (STZ), a rat model commonly used to mimic sporadic AD. ICV-STZ induced significant astrogliosis in the commissural part of the nucleus tractus solitarii, an area highly involved in respiration control. The astrogliosis was identified by a significant increase in S100B-immunofluorescence that is similar to the astrogliosis found in the CA1 region of the hippocampus. Using plethysmography, the control group displayed a typical age-dependent decrease of ventilation that was absent in the STZ rat group. This is indicative of elevated minute ventilation at rest after STZ treatment. Peripheral chemoreflex responses were significantly blunted in STZ rats as seen by a reduced respiratory rate and minute ventilation to hypoxia. Central chemoreflex responses to hypercapnia, on the other hand, only decreased in respiratory rate following STZ treatment. Overall, our results show that ICV-STZ induces respiratory dysfunction at rest and in response to hypoxia. This provides a new tool to study the underlying mechanisms of breathing disorders in clinical AD.