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: 7458636
• 负责人: P. Hemachandra Reddy
• 金额: $ 30.94万
• 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/7458636
• 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; Other Finding; Pathology; Patients; Production; Proteins; Reactive Oxygen Species; Research; Research Personnel; Rodent Model; Role; Testing; Tg2576; Time; Toxic effect; Transcriptional Activation; 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; 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预防阿尔茨海默病（AD）发作的神经保护策略制定合理的基础。最近，多项证据表明，年龄相关的活性氧 (ROS) 与 AD 等迟发性神经退行性疾病中的线粒体氧化损伤有关。线粒体功能研究显示AD患者死后大脑中线粒体异常，以及AD症状前患者大脑影像学研究表明，脑能量代谢缺陷可能是AD发生和进展的关键因素。最近的全球基因表达研究表明，AD 转基因小鼠品系 Tg2576 的 2、5 和 18 个月大小鼠的线粒体基因上调，表明突变的淀粉样前体蛋白/Abeta 可能会损害线粒体能量代谢。 APP/A?) 并且线粒体基因表达的上调可能是对突变 APP/A? 的补偿反应毒性。此外，初步生化研究表明，与野生型小鼠相比，Tg2576小鼠的过氧化氢、氧化DNA和蛋白质有所增加，这也为AD小鼠发生氧化损伤提供了支持。这些研究还揭示了 4kDa A?与线粒体相关，负责产生 ROS 和线粒体功能障碍。进一步，对Tg2576小鼠的研究发现，可溶性A？与 2 个月大的 Tg2576 小鼠中的过氧化氢显着相关。总而言之，所有这些结果表明突变体 APP 和/或 A?在疾病进展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反应。拟议的研究将追求以下假设：A？是产生ROS和线粒体功能障碍的主要因素。提出以下目标来研究这一假设： 目标 1. 确定线粒体功能障碍是否会触发 Tg2576 小鼠的线粒体基因表达；目标 2. 确定 APP 和/或 A 是否突变？导致 Tg2576 小鼠氧化损伤；目标 3. 确定线粒体靶向抗氧化剂过氧化氢酶是否会降低 ROS、线粒体毒性和 A？ Tg2576 小鼠和 APP 过表达细胞系模型中的水平。目标 1 和 2 将调查 APP 和/或 A 如何突变？与 Tg2576 小鼠整个生命周期的线粒体功能障碍有关。目标 3 将通过表征线粒体氧化损伤的神经保护机制来对该假设进行机制检验，并使我们更接近确定 AD 的新疗法。