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H2 O2是线粒体产生活性氧的主要形式。最近的数据表明，线粒体H2 O2增加与阿尔茨海默病（AD）的发病机制有关，并可能通过诱导氧化损伤和改变细胞信号传导影响淀粉样蛋白生成来促进AD的发病机制。虽然有针对性地清除线粒体ROS已被提出作为AD的预防/治疗策略，但减少线粒体H2 O2是否可以延缓AD的发病机制尚不清楚。过氧化物氧还蛋白3（Peroxiredoxin 3，Prdx 3/Prx 3）是一种专门清除线粒体中H2 O2的过氧化物酶，也被认为对保护神经退行性疾病很重要。我们最近产生了过表达Prdx 3的转基因小鼠，我们的数据表明，过表达Prdx 3的转基因小鼠线粒体H2 O2水平降低，这与线粒体氧化损伤减少和脑中2-和3-分泌酶活性降低有关。因此，我们的研究结果表明，过表达Prdx 3是有效的减少线粒体H2 O2和过表达Prdx 3的转基因小鼠将使我们能够测试的预防和治疗潜力，减少线粒体H2 O2 AD。本研究利用过表达Prdx 3的APP转基因小鼠，验证以下假设：通过过表达Prdx 3减少线粒体H2 O2，可以改善线粒体功能，改善认知障碍，减少淀粉样变性。该假设将在四个具体目标中进行测试：1。确定减少线粒体H2 O2是否改善APP转基因小鼠的线粒体功能。2.确定减少线粒体H2 O2是否减少APP转基因小鼠的氧化损伤并改变细胞信号传导。3.确定减少线粒体H2 O2是否能改善APP转基因小鼠的认知障碍并减少淀粉样蛋白生成。4.确定减少线粒体H2 O2是否可以延缓AD发病后的进展。在具体目标4中，将产生具有Prdx 3的可诱导过表达的新型APP转基因小鼠模型，并用于确定Prdx 3的过表达是否可以减缓或逆转这些不良表型发展后认知缺陷和A（）积累的进展。从该项目收集的数据将提供关于减少线粒体H2 O2是否有效延缓AD发病机制以及Prdx 3是否可以作为AD预防和治疗的靶点的第一个直接证据。 老年痴呆症对退伍军人特别重要，因为老年痴呆症的发病率似乎因我们的男女军人在部署期间遇到的条件而升高，如创伤性脑损伤。这项研究收集的数据可能会导致新的预防和治疗方法的AD，这将有利于我们的军人男女。1 公共卫生关系： 阿尔茨海默病的风险增加是我们军人的一个严重问题。这项研究旨在测试一种新的预防和治疗策略对阿尔茨海默病的有效性。1