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

阿尔茨海默病的呼吸功能障碍及其与脑干内氧化损伤的联系。

• 批准号: 10112668
• 负责人: Tim D. Ostrowski
• 金额: $ 38.74万
• 依托单位: A.T. STILL UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112668
• 关键词: Acute; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Animal Model; Antioxidants; Biogenesis; Brain; Brain Stem; Brain region; Breathing; Chronic; Clinical Trials; Cognitive deficits; Development; Diet; Disease Marker; Electrophysiology (science); Etiology; Excision; Exhibits; Exposure to; Goals; Health; Heart failure; High Prevalence; Human; Hyperactivity; Hypoxia; Impairment; In Vitro; Lead; Link; Memory; Mental Depression; Methodology; Methods; Microinjections; Modeling; Molecular; Monitor; Morphology; Neurofibrillary Tangles; Neurons; Nucleus solitarius; Onset of illness; Output; Oxidation-Reduction; Pathogenesis; Pathologic; Patients; Pattern; Peripheral; Pharmacology; Play; Property; Prosencephalon; Quality of life; Rattus; Reactive Oxygen Species; Research; Respiration; Respiration Disorders; Role; Senile Plaques; Sleep Apnea Syndromes; Sleep Disorders; Slice; Structure; Students; Symptoms; Synapses; System; Testing; Therapeutic; Translating; Up-Regulation; cell type; cellular targeting; effective therapy; experimental study; graduate student; improved; in vivo; inhibitor/antagonist; innovation; neuron loss; neurophysiology; novel strategies; oxidation; oxidative damage; patch clamp; repaired; respiratory; respiratory health; response; subcellular targeting; targeted treatment; tau Proteins; tau-1; treatment strategy; undergraduate student

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.

项目摘要/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。没有治愈方法并且 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）对于 呼吸控制和 AD 患者的 nTS 表现出明显的病理改变，类似于在 前脑与记忆相关的大脑结构。此外，活性氧（ROS）紧密结合 与 AD 病因相关的 nTS 内的 ROS 会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。 通过使用密切模仿人类 AD 和相关呼吸功能障碍的模型，这项研究将 专注于呼吸控制中改变的 nTS 处理并检查潜在的神经生理学 机制。目前使用抗氧化剂来减少 ROS 负荷的 AD 治疗在 AD 患者中失败了。尽管 过量的ROS可以被清除，氧化损伤盛行并继续诱发AD症状。 ROS 的特定亚细胞靶标尚未得到研究。我们的中心假设是 ROS- 诱导的 nTS 活性增强是 AD 呼吸功能障碍以及氧化损伤修复的基础 除了降低ROS之外，还需要有效治疗阿尔茨海默病的呼吸功能障碍。 该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 的变化。我们将检查 nTS 的以下方面 主要细胞类型、化学感应终端、候选 AD 标记物和基础活性的变化 与AD。为了分析 nTS 在 AD 中的功能作用，我们将从药理学角度改变 nTS 活性（使用 显微注射到 nTS 中）并使用体内电生理记录监测呼吸输出 麻醉的老鼠。这些改变背后的神经生理学机制将通过体外研究来解决 nTS 切片中的膜片钳记录。化学传入突触输入、nTS 神经元特性和 AD 中潜在的离子电流将被检查。我们还将在 nTS 中识别 ROS 引起的损伤 广告（目标 2）。将分析 ROS 水平、抗氧化防御系统和 nTS 的氧化态。这 AD 衍生的 ROS 在 nTS 中的特殊作用将通过 nTS 中抗氧化剂的局部上调来检查。 慢性 AD-ROS 及其去除（类似于当前的治疗策略）的功能影响将是 通过急性 nTS 显微注射抗氧化剂进行鉴定。然后对ROS敏感目标进行紧急救援 阐明氧化损伤对 AD 呼吸功能障碍的影响。我们的研究将首先 解决 AD 危及生命的呼吸系统并发症的机制根源。我们的结果可能会 促进针对 AD 中 ROS 诱导损伤的新策略的开发，以改善呼吸系统健康。