AB AND NADPH OXIDASE IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER'S DISEASE

AB 和 NADPH 氧化酶在轻度认知障碍和阿尔茨海默病中的作用

• 批准号: 7805523
• 负责人: ANNADORA J BRUCE-KELLER
• 金额: $ 26.18万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7805523
• 关键词: 4 hydroxynonenal; APP-PS1; Ablation; Affect; Age; Age-Months; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Attenuated; Automobile Driving; Biochemical; Brain; Brain region; Cell Death; Cerebellum; Cessation of life; Characteristics; Clinical; Data; Dementia; Deposition; Diagnostic; Disease; Dose; Free Radicals; Frontotemporal Dementia; Future; Genetic; Genetic Techniques; Hippocampus (Brain); Histological Techniques; Human; Impairment; In Vitro; Inferior; Inflammation; Inflammatory; Injury; Knock-in Mouse; Link; Lobule; Measures; Mediating; Methods; Microglia; Mitochondria; Modeling; Monitor; Mus; NADPH Oxidase; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neuronal Injury; Neurons; Oxidation-Reduction; Oxidative Stress; Parietal; Pathogenesis; Pathology; Patients; Physiological; Population; Production; Proteins; RNA; Reactive Oxygen Species; Regulation; Respiratory Burst; Role; Senile Plaques; Signal Transduction; Societies; Specimen; Staging; Structure of middle temporal gyrus; Sum; System; Testing; Therapeutic Intervention; Time; Tissue Banking; Tissue Banks; Tissues; Transgenic Mice; acetovanillone; age related; amyloidogenesis; attenuation; base; disorder control; in vivo; indexing; inhibitor/antagonist; innovation; mild neurocognitive impairment; mind control; mouse model; neuron loss; neuropsychological; neurotoxic; neurotoxicity; nitration; novel; novel strategies; oxidation; pre-clinical; research study; response

Alzheimer's disease (AD) is the major age-related dementia, and is expected to take an increasing toll on society as the population ages. Histopathologically, while the diagnostic criterion for AD is the presence of amyloid-containing plaques and neurofibrilliary tangles, AD brains are typified by increased oxidative stress and focal neuronal death. While the exact relationship between beta amyloid (AP) deposition, oxidative stress, and neuronal injury is still unresolved, increasing evidence suggests that the NADPH oxidase system may be altered in AD and in response to Ap. NADPH oxidase (NOX), originally described as the main component of the leukocyte oxidative burst, produces reactive oxygen species (ROS) that are involved in both intracellular signaling and oxidative stress. NOX expression has been established in neurons, thus raising the possibility that aberrant activation of neuronal NOX by toxic forms of A(3 could contribute to ADrelated neuronal alterations. The focus of this project is to test the hypothesis that sustained activation of NOX by Ap triggers a pernicious cascade linking increases in ROS production to altered intracellular redoxbased signaling and oxidative stress, culminating in neuron degeneration and death. The specific aims to test this hypothesis are as follows: 1) To test the hypothesis that NOX activity is increased during the progression of AD; 2) To test the hypothesis that NOX activity is increased in response to increasing Ap deposition in a specific APP/PS1 knock-in mouse model of amyloidogenesis; 3) To test the hypothesis that toxic forms of Ap increase neuronal oxidative stress and cell death via NOX; 4) To test the hypothesis that microglial NOX activation exacerbates neuronal responses to AP; and 5) To test the hypothesis that genetic or pharmacologic ablation of NOX in the APP/PS1 transgenic mice attenuates oxidative stress and Ap pathogenesis in vivo. The proposed experiments will make use of our extensive and well-characterized tissue bank of human brain specimens, as well as a novel and highly relevant mouse model of beta amyloid pathogenesis. Finally, studies will determine the specific effects of distinct physiological forms of AP(1-40/1- 42/oligomer/fibrillar) on NOX activation both in vitro and in vivo. Completion of these studies will result in a more thorough understanding of the relationship between Ap deposition and AD-related neuronal pathology, and could highlight an innovative and highly promising target for therapeutic intervention in AD.

阿尔茨海默氏病（AD）是与年龄相关的主要痴呆症，预计会越来越多 社会作为人口年龄。在组织病理学上，虽然AD的诊断标准是存在 含淀粉样蛋白的斑块和神经纤维缠结，AD大脑的氧化应激量增加 和局灶性神经元死亡。而β-淀粉样蛋白（AP）沉积之间的确切关系，氧化 压力和神经元损伤仍未解决，越来越多的证据表明NADPH氧化酶系统 可能会改变AD并响应AP。 NADPH氧化酶（NOX），最初被描述为主要 白细胞氧化爆发的成分，产生活性氧（ROS） 细胞内信号传导和氧化应激。 NOx表达已在神经元中建立，因此 提高了通过a的有毒形式对神经元NOX的异常激活的可能性（3可能有助于融合 神经元改变。该项目的重点是检验以下假设 AP的NOX触发了ROS产生的有害级联链接增加与基于细胞内氧化还原的变化 信号传导和氧化应激，最终导致神经元变性和死亡。具体目的 检验该假设如下：1）检验以下假设： AD的进展； 2）检验假设NOX活性随着AP的增加而增加 在特定的APP/PS1中沉积淀粉样生成的小鼠模型； 3）检验以下假设 AP的有毒形式增加了神经元氧化应激和通过NOX的细胞死亡； 4）检验以下假设 小胶质细胞NOX激活加剧了对AP的神经元反应； 5）检验遗传的假设 或在APP/PS1转基因小鼠中NOX的药理消融会减弱氧化应激和AP 体内发病机理。拟议的实验将利用我们的广泛和良好的特征 人类脑标本的组织库，以及一种新型且高度相关的β淀粉样蛋白小鼠模型 发病。最后，研究将确定AP的不同生理形式的特定影响（1-40/1- 42/低聚物/原纤维）在体外和体内都在NOX激活上。这些研究的完成将导致 对AP沉积与广告相关的神经元病理之间的关系更彻底地了解， 并可以强调在AD中进行治疗干预的创新且高度有希望的目标。