The majority of Alzheimer's disease (AD) patients exhibit respiratory dysfunction that can lead to poor quality of life and various health complications. There is no cure and mechanisms behind these changes are unknown. AD pathology affects the entire brain, including brainstem centers important for respiration. Within the brainstem, the nucleus tractus solitarii (nTS) is essential in respiratory control and AD patients show clear pathological alterations in the nTS similar to those seen in memory-related brain structures of the forebrain. Furthermore, reactive oxygen species (ROS) are tightly associated with the etiology of AD and ROS within the nTS critically alter neuronal function. However, the consequences of ROS and altered nTS activity for respiratory dysfunction in Alzheimer's disease are unknown. By using a model that closely mimics human AD and the associated respiratory dysfunction, this study will focus on altered nTS processing in respiratory control and examine the underlying neurophysiological mechanisms. Current AD treatments using antioxidants to decrease ROS load are failing in AD patients. While excessive ROS can be removed, the oxidative damage prevails and continues to induce AD symptoms. Specific sub-cellular targets of ROS have not been examined yet. Our central HYPOTHESIS is that ROS- induced augmented nTS-activity underlies respiratory dysfunction in AD and that repair of oxidative damage in addition to lowering ROS is needed for effective treatment of respiratory dysfunction in Alzheimer's disease. This hypothesis will be addressed by determining the morphological, functional, and mechanistic alterations within the chemosensitive nTS in Alzheimer's disease (AIM 1). We will examine the nTS in regard to changes in major cell types, chemosensory terminals, candidate AD markers, and basal activity when inflicted with AD. To analyze the functional role of the nTS in AD, we will pharmacologically alter nTS activity (using microinjections into the nTS) and monitor respiratory output using in vivo electrophysiological recordings in anesthetized rats. The neurophysiological mechanisms behind these alterations will be addressed with in vitro patch clamp recordings in nTS slices. Changes in chemoafferent synaptic input, nTS neuronal properties, and underlying ionic currents in AD will be examined. We will also identify ROS-induced damage within the nTS in AD (AIM 2). ROS levels, antioxidant defense systems, and oxidation state of the nTS will be analyzed. The particular role of AD-derived ROS in the nTS will be examined by local upregulation of antioxidants in the nTS. Functional implications of chronic AD-ROS and their removal (similar to current therapeutic strategies) will be identified using acute nTS microinjections of antioxidants. Acute rescue of ROS-sensitive targets will then elucidate the contribution of oxidative damage to respiratory dysfunction in AD. Our study will be the first to address the mechanistic origin of life-threatening respiratory complications with AD. Our results will likely facilitate development of novel strategies targeting ROS-induced damage in AD to improve respiratory health.
Sleep-disordered breathing (SDB) is highly associated with Alzheimer?s disease (AD) and dramatically affects the health of patients with AD. Current AD treatments remove the factor producing neuronal damage but do not remove or repair the damage itself. Using an animal model that closely resembles the symptoms of AD in humans, we have begun to identify the affected brain region underlying impaired respiratory control. This study will identify key targets and mechanisms of AD in this region, which can be translated into targeted treatment strategies to improve the lives of patients with AD.
