The preventive and therapeutic potential of reducing mitochondrial H2O2 for AD

减少线粒体 H2O2 对 AD 的预防和治疗潜力

• 批准号: 7683614
• 负责人: QITAO RAN
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683614
• 关键词: Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Brain; Cognition; Complex; DNA; Data; Development; Effectiveness; Excision; Frequencies; Functional disorder; Hydrogen Peroxide; Impaired cognition; Impairment; Incidence; Lead; Learning; Lipids; Measures; Membrane Potentials; Memory; Military Personnel; Mitochondria; Mus; Neurodegenerative Disorders; Neurons; Onset of illness; Oxidation-Reduction; PRDX3 peroxidase; Pathogenesis; Patients; Peroxidases; Phenotype; Play; Population; Prevention therapy; Preventive; Production; Proteins; Reactive Oxygen Species; Reduced Glutathione; Research; Respiration; Respiratory Chain; Role; Services; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Transgenic Mice; Traumatic Brain Injury; Veterans; Woman; abeta accumulation; abstracting; alpha secretase; amyloidogenesis; design; glutathione peroxidase; improved; macromolecule; membrane activity; men; mitochondrial DNA mutation; mouse model; novel; overexpression; oxidative damage; peroxiredoxin; public health relevance; secretase

DESCRIPTION (provided by applicant): Abstract H2O2 is a major form of reactive oxygen species (ROS) produced by mitochondria. Recent data indicate that increased mitochondrial H2O2 is associated with pathogenesis of Alzheimer's disease (AD) and could facilitate AD pathogenesis by inducing oxidative damage and by altering cell signaling to affect amyloidogenesis. Although targeted removal of mitochondrial ROS has been proposed as a preventive/therapeutic strategy for AD, whether reducing mitochondrial H2O2 can retard pathogenesis of AD is unknown. Peroxiredoxin 3 (Prdx3/Prx3) is a peroxidase specializing in scavenging H2O2 in mitochondria and is also implicated to be important for protection against neurodegenerative diseases. We have recently generated transgenic mice overexpressing Prdx3, and our data indicate that transgenic mice overexpressing Prdx3 have reduced mitochondrial H2O2 levels that are correlated with reduced mitochondrial oxidative damage and decreased activities of 2- and 3- secretases in brain. Thus, our results indicate that overexpression of Prdx3 is effective in reducing mitochondrial H2O2 and that transgenic mice overexpressing Prdx3 will allow us to test the preventive and therapeutic potential of reducing mitochondrial H2O2 for AD. Using APP transgenic mice overexpressing Prdx3 in this project, we will test the following hypothesis: reducing mitochondrial H2O2 by overexpression of Prdx3 will improve mitochondria functions, ameliorate cognition impairment and reduce amyloidogenesis. The hypothesis will be tested in four Specific Objectives: 1. To determine if reducing mitochondrial H2O2 improves mitochondria functions in APP transgenic mice. 2. To determine if reducing mitochondrial H2O2 reduces oxidative damage and changes cell signaling in APP transgenic mice. 3. To determine if reducing mitochondrial H2O2 ameliorates cognitive impairment and decreases amyloidogenesis in APP transgenic mice. 4. To determine if reducing mitochondrial H2O2 can retard progression of AD after the onset of disease. In Specific Objective 4, a novel APP transgenic mouse model with inducible overexpression of Prdx3 will be generated and used to determine whether overexpressing of Prdx3 can slow or reverse the progression of cognition deficit and A( accumulation after the development of these adverse phenotypes. The data collected from this project will provide the first direct evidence about whether reducing mitochondrial H2O2 is effective for retarding AD pathogenesis and whether Prdx3 could serve as a target for AD prevention and therapy. Alzheimer's disease is of special importance to the veteran population because the incidence of Alzheimer's disease appears to be elevated by conditions encountered by our service men and women during deployment such as traumatic brain injury. Data collected in this study may lead to new preventive and therapeutic approaches for AD, which will benefit our military service men and women. 1 PUBLIC HEALTH RELEVANCE: Project Narrative Increased risk of Alzheimer's disease is a serious concern for our military service men and women. This study is designed to test the effectiveness of a novel prevention and therapy strategy for Alzheimer's disease. 1

描述（由申请人提供）： 摘要H2O2是线粒体产生的活性氧（ROS）的一种主要形式。最近的数据表明，线粒体H2O2的增加与阿尔茨海默氏病（AD）的发病机理有关，并且可以通过诱导氧化损伤和改变细胞信号来影响淀粉样生成来促进AD发病机理。尽管已提出有针对性的线粒体ROS作为AD的预防/治疗策略，但还不清楚线粒体H2O2是否会延迟AD的发病机理。过氧蛋白3（PRDX3/PRX3）是一种过氧化物酶，专门从事线粒体清除H2O2，也牵涉到对保护神经退行性疾病的重要性。我们最近产生了过表达PRDX3的转基因小鼠，我们的数据表明，过表达PRDX3的转基因小鼠的线粒体H2O2水平降低，与脑部2-和3个脑中2-和3个秘密的活性降低相关的线粒体H2O2水平。因此，我们的结果表明，PRDX3的过表达可有效减少H2O2，并且过表达PRDX3的转基因小鼠将使我们能够测试减少AD的线粒体H2O2的预防和治疗潜力。使用该项目中过表达PRDX3的APP转基因小鼠，我们将测试以下假设：通过过表达PRDX3来减少线粒体H2O2将改善线粒体功能，减轻认知障碍并减少淀粉样蛋白生成。该假设将以四个特定目标进行检验：1。确定减少线粒体H2O2是否可以改善APP转基因小鼠的线粒体功能。 2。确定减少线粒体H2O2是否会减少APP转基因小鼠中细胞信号的氧化损伤。 3。确定减少线粒体H2O2是否可以改善认知障碍并减少APP转基因小鼠的淀粉样生成。 4。确定减少线粒体H2O2是否会在疾病发作后阻碍AD的进展。 In Specific Objective 4, a novel APP transgenic mouse model with inducible overexpression of Prdx3 will be generated and used to determine whether overexpressing of Prdx3 can slow or reverse the progression of cognition deficit and A( accumulation after the development of these adverse phenotypes. The data collected from this project will provide the first direct evidence about whether reducing mitochondrial H2O2 is effective for retarding AD pathogenesis and whether Prdx3可以作为预防和治疗的目标 公共卫生相关性： 对于我们的兵役男人和女人来说，叙事的叙述增加了阿尔茨海默氏病的风险是一个严重关注的问题。这项研究旨在测试阿尔茨海默氏病的新型预防和治疗策略的有效性。 1