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

项目总结/摘要：大多数阿尔茨海默病（AD）患者表现出呼吸系统疾病， 功能障碍，可能导致生活质量差和各种健康并发症。无药可救， 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 重要的呼吸中心。在脑干内，孤束核（nTS）是必不可少的， 呼吸控制和AD患者的nTS显示出明显的病理学改变，与在 前脑与记忆有关的脑结构。此外，活性氧（ROS）是紧密结合的。 与AD的病因学相关，nTS内的ROS严重改变神经元功能。但 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。 通过使用密切模拟人类AD和相关呼吸功能障碍的模型，本研究将 关注呼吸控制中nTS处理的改变，并检查潜在的神经生理学 机制等目前使用抗氧化剂降低ROS负荷的AD治疗在AD患者中失败。而 过量的ROS可以被去除，氧化损伤占优势并继续诱导AD症状。 ROS的特异性亚细胞靶点尚未研究。我们的中心假设是，ROS- 诱导增强的nTS活性是AD呼吸功能障碍的基础， 除了降低ROS外，还需要有效治疗阿尔茨海默病中的呼吸功能障碍。 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（AIM 1）中化学敏感性nTS内的改变。我们将在以下方面检查nTS 主要细胞类型、化学感受末梢、候选AD标志物和基础活动的变化 与AD为了分析nTS在AD中的功能作用，我们将改变nTS活性（使用 微注射到nTS中），并使用体内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在体外 nTS切片的膜片钳记录。化学传入突触输入、nTS神经元特性和 将检查AD中的潜在离子电流。我们还将确定ROS引起的损害内的nTS， AD（AIM 2）。将分析ROS水平、抗氧化防御系统和nTS的氧化状态。的 将通过nTS中抗氧化剂的局部上调来检查AD衍生的活性氧在nTS中的特殊作用。 慢性AD-ROS及其清除（类似于当前的治疗策略）的功能影响将在下文中讨论。 使用急性nTS微量注射抗氧化剂鉴定。对ROS敏感靶点的急性抢救将 阐明氧化损伤对AD呼吸功能障碍的作用。我们的研究将是第一个 解决AD危及生命的呼吸系统并发症的机制起源。我们的结果可能会 促进开发针对AD中ROS诱导的损伤的新策略，以改善呼吸系统健康。

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.