Abeta Toxicity, ROS and Mitochondrial Dysfunction in Aging/Alzheimer's Disease

衰老/阿尔茨海默病中的 Abeta 毒性、ROS 和线粒体功能障碍

• 批准号: 7884562
• 负责人: P. Hemachandra Reddy
• 金额: $ 30.63万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884562
• 关键词: Adenosine Triphosphate; Affect; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Antioxidants; Autopsy; Biochemical; Brain; Brain region; Cell Line; Cerebrum; DNA; Defect; Development; Disease; Disease Progression; Electron Transport; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Exhibits; Free Radicals; Future; Gene Expression; Generations; Genes; Goals; High Pressure Liquid Chromatography; Hydrogen Peroxide; Image; Lead; Longevity; Maintenance; Measures; Mitochondria; Modeling; Mus; Neurodegenerative Disorders; Neurons; Pathology; Patients; Production; Proteins; Reactive Oxygen Species; Research; Research Personnel; Rodent Model; Role; Testing; Tg2576; Time; Toxic effect; Transgenic Animals; Transgenic Mice; Up-Regulation; Wild Type Mouse; Work; abeta toxicity; age related; base; beta-site APP cleaving enzyme 1; catalase; cognitive change; cytochrome c oxidase; mitochondrial dysfunction; mouse model; mutant; novel; oxidation; oxidative damage; prevent; programs; response; rosin

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to develop a rational basis for neuroprotective strategies to delay or to prevent the onset of Alzheimer's disease (AD). Recently, several lines of evidence have revealed that age-related reactive oxygen species (ROS) is associated with mitochondrial oxidative damage in late-onset neurodegenerative diseases such as AD. Studies of mitochondrial function have shown mitochondrial abnormalities in postmortem brains in AD patients and imaging studies of brains from presymptomatic AD patients, suggesting that defects in cerebral energy metabolism may be a key factor in the development and progression of AD. Recent global gene expression studies have revealed an up-regulation of mitochondrial genes in 2-, 5- and 18-month-old mice from AD transgenic mouse line Tg2576, suggesting that mitochondria energy metabolism may be impaired by mutant amyloid precursor protein/Abeta (APP/A?) and that the up-regulation of mitochondrial gene expression may be a compensatory response to mutant APP/A? toxicity. In addition, preliminary biochemical studies have revealed increases in hydrogen peroxide, oxidized DNA and proteins in Tg2576 mice compared to wild-type mice, also providing support that oxidative damage occurs in the AD mice. These studies have also revealed that 4kDa A? is associated with mitochondria and is responsible for generating ROS and mitochondrial dysfunction. Further, the studies of Tg2576 mice have found that soluble A? significantly correlates with hydrogen peroxide in 2-month-old Tg2576 mice. Taken together, all these results suggest that mutant APP and/or A? generates free radicals and mitochondrial dysfunction early in disease progression and that the up-regulation of mitochondrial genes may be a compensatory response to mitochondrial toxicity. The proposed studies will pursue the hypothesis that A? is a major factor in generating ROS and mitochondrial dysfunction. The following Aims are proposed to investigate this hypothesis: Aim 1. To determine whether mitochondrial dysfunction triggers mitochondrial gene expression in Tg2576 mice; Aim 2. To determine whether mutant APP and/or A? leads to oxidative damage in Tg2576 mice; and Aim 3. To determine whether mitochondrially targeted antioxidant catalase reduces ROS, mitochondrial toxicity and A? levels in Tg2576 mice and in an APP over-expressed cell-line model. Aims 1 and 2 will investigate how mutant APP and/or A? relate to mitochondrial dysfunction throughout the lifespan of Tg2576 mice. Aim 3 will provide a mechanistic test of the hypothesis by characterizing neuroprotective mechanisms of mitochondrial oxidative damage, and will take us closer to identifying novel therapies of AD.

描述（由申请人提供）：拟议研究的长期目标是为延迟或防止阿尔茨海默氏病（AD）的神经保护策略建立合理的基础。最近，几种证据表明，与年龄相关的活性氧（ROS）与晚期神经退行性疾病（如AD）中的线粒体氧化损伤有关。线粒体功能的研究表明，AD患者的验尸大脑中的线粒体异常以及对预性AD患者的大脑的成像研究，这表明脑能量代谢缺陷可能是AD发育和进展的关键因素。 Recent global gene expression studies have revealed an up-regulation of mitochondrial genes in 2-, 5- and 18-month-old mice from AD transgenic mouse line Tg2576, suggesting that mitochondria energy metabolism may be impaired by mutant amyloid precursor protein/Abeta (APP/A?) and that the up-regulation of mitochondrial gene expression may be a compensatory response to mutant应用程序/A？毒性。此外，与野生型小鼠相比，初步生化研究表明，TG2576小鼠的过氧化氢，氧化的DNA和蛋白质增加，也提供了支持AD小鼠中氧化损伤的支持。这些研究还揭示了4KDA A？与线粒体有关，负责产生ROS和线粒体功能障碍。此外，对TG2576小鼠的研究发现可溶性A？在2个月大的TG2576小鼠中，与过氧化氢显着相关。综上所述，所有这些结果表明突变应用程序和/或A？在疾病进展的早期产生自由基和线粒体功能障碍，线粒体基因的上调可能是对线粒体毒性的补偿性反应。拟议的研究将提出一个假设。是产生ROS和线粒体功能障碍的主要因素。提出了以下目的来研究这一假设：目的1。确定线粒体功能障碍是否触发TG2576小鼠中的线粒体基因表达；目标2。确定突变应用程序和/或A？导致TG2576小鼠的氧化损伤；目标3。确定线粒体靶向的抗氧化过氧化氢酶是否会降低ROS，线粒体毒性和A？ TG2576小鼠和应用过表达的单元线模型中的水平。目标1和2将研究突变应用程序和/或A？在TG2576小鼠的整个生命周期中，与线粒体功能障碍有关。 AIM 3将通过表征线粒体氧化损伤的神经保护机制来提供假设的机械测试，并将使我们更接近鉴定AD的新疗法。