PROJECT SUMMARY/ABSTRACT: 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.