Respiratory dysfunction in Alzheimer's disease and its link to oxidative damage within the brain stem.

项目摘要/摘要：大多数阿尔茨海默病(AD)患者表现为呼吸道 功能障碍会导致生活质量下降和各种健康并发症。没有解药，而且 这些变化背后的机制尚不清楚。AD病理影响整个大脑，包括脑干 对呼吸很重要的中枢。在脑干内，孤束核(NTS)是 呼吸控制和AD患者的NTS显示出明显的病理改变，类似于 前脑与记忆相关的脑结构。此外，活性氧物种(ROS)紧密地 与AD和NTS内ROS的病因学相关，严重改变神经元功能。然而， ROS和NTS活性改变对阿尔茨海默病呼吸功能障碍的影响尚不清楚。 通过使用一个非常接近模拟人类AD和相关呼吸功能障碍的模型，这项研究将 关注呼吸控制中NTS处理的改变，并检查潜在的神经生理学 机械装置。目前使用抗氧化剂降低ROS负荷的AD治疗方法在AD患者中失败。而当 过量的ROS可以被清除，氧化损伤占上风，并继续引发AD症状。 ROS的特定亚细胞靶点还没有被研究。我们的中心假设是ROS- 诱导NTS活性增强是AD呼吸功能障碍和氧化损伤修复的基础 除了降低ROS外，还需要有效治疗阿尔茨海默病的呼吸功能障碍。 这一假设将通过确定形态、功能和机制来解决 阿尔茨海默病患者对药物敏感的NTS的变化(目标1)。我们会就以下方面研究新界南区 主要细胞类型、化学感觉终末、候选AD标志物和基础活动的变化 使用AD。为了分析NTS在AD中的功能作用，我们将从药物上改变NTS的活性(使用 NTS内微量注射)，并使用活体电生理记录监测呼吸输出 麻醉大鼠。这些改变背后的神经生理机制将通过体外实验来解决。 NTS切片中的膜片钳记录。化学传入突触输入，NTS神经元特性的变化，以及 我们将研究AD中潜在的离子电流。我们还将在NTS中确定ROS导致的损害 AD(目标2)。将对NTS的ROS水平、抗氧化防御系统和氧化状态进行分析。这个 AD来源的ROS在NTS中的特殊作用将通过局部上调NTS中的抗氧化剂来检验。 慢性AD-ROS及其清除的功能影响(类似于当前的治疗策略)将是 通过急性NTS微量注射抗氧化剂进行鉴定。对ROS敏感目标的紧急救援将 阐明氧化损伤在AD呼吸功能障碍中的作用。我们的研究将是第一个 阐述威胁生命的阿尔茨海默病呼吸道并发症的机制根源。我们的结果很可能 促进针对ROS诱导的AD损伤的新策略的开发，以改善呼吸健康。

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.