Mitochondrial ROS in environmental toxin-induced AD pathogenesis

环境毒素诱导的 AD 发病机制中的线粒体 ROS

• 批准号: 8239669
• 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: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239669
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein Precursor; Animal Model; Antioxidants; Astrocytes; Attenuated; Cells; Cognition; Crossbreeding; Data; Dementia; Enzymes; Epidemiology; Etiology; Excision; Exposure to; Generations; Genetic Recombination; Goals; Hydrogen Peroxide; Impaired cognition; Long-Term Effects; Measures; Mediating; Microglia; Military Personnel; Mitochondria; Mus; Neuroglia; Neurons; PRDX3 peroxidase; Paraquat; Pathogenesis; Personal Satisfaction; Pesticides; Play; Preventive Intervention; Reactive Oxygen Species; Risk; Services; Tamoxifen; Testing; Therapeutic Intervention; Toxic Environmental Substances; Toxin; Transgenic Mice; Transgenic Model; Veterans; Woman; amyloidogenesis; brain cell; cell type; improved; in vivo; men; mouse model; novel; overexpression; peroxiredoxin; pesticide exposure

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common dementia affecting millions of people. Although the etiology of the majority of AD cases remains unclear, epidemiological data indicate that exposure to environmental toxins such as pesticides increases the risk for developing AD. We have recently showed that exposure to pesticide paraquat exacerbated cognitive impairment and increased A¿ accumulation in AD animal models and that overexpression of peroxiredoxin 3 (Prdx3), a mitochondrial antioxidant defense enzyme important for H2O2 removal, attenuated paraquat-induced cognitive impairment and A¿ accumulation. Our results thus suggest that the increased risk of AD conferred by pesticide exposure is mediated by increased generation of mitochondrial reactive oxygen species (ROS). However, the mechanism of mitochondrial ROS in mediating cognitive impairment and A¿ accumulation induced by paraquat exposure remains unclear. In this study, we will generate APP transgenic mice with overexpression of Prdx3, including APP transgenic mice with inducible overexpression of Prdx3 and APP transgenic mice with overexpression of Prdx3 in specific brain cell types such as neurons, astrocytes and microglia. We will then study the effects of paraquat exposure on cognition and amyloidogenesis in APP transgenic models with overexpression of Prdx3 and control APP transgenic mice. The data gathered will provide powerful evidence of the detailed mechanism of mitochondrial ROS in mediating paraquat- induced cognitive impairment and A¿ accumulation. The overall hypothesis tested in this study is: Increased generation of mitochondrial ROS by neurons and glial cells plays a key role in mediating cognitive impairment and A¿ accumulation induced by exposure to an environmental toxin. The hypothesis will be tested by three Specific Aims. Aim 1, to determine the long-term effects of paraquat exposure on cognition and A¿ accumulation in AD mouse models with or without Prdx3 overexpression; Aim 2, to determine the effect of Prdx3 overexpression before or after paraquat exposure on attenuating paraquat-induced cognitive impairment and A¿ accumulation; Aim 3, to determine the effect of Prdx3 overexpression specifically in neurons, astrocytes or microglia on attenuating paraquat-induced cognitive impairment and A¿ accumulation. Our military service men and women are exposed to a variety of toxins such as pesticides during deployment, so the increased risk of AD conferred by exposure to toxins is a serious concern for the well-being of our military service men and women. The data gathered in this study will provide valuable information for developing preventive and therapeutic interventions to reduce the risk of AD conferred by toxin exposure, thereby benefitting our veterans.

描述（由申请人提供）： 阿尔茨海默病（AD）是影响数百万人的最常见的痴呆症。虽然大多数AD病例的病因尚不清楚，但流行病学数据表明，暴露于环境毒素（如农药）会增加发生AD的风险。我们最近发现，暴露于农药百草枯加剧了AD动物模型中的认知障碍并增加了A？积累，并且过表达过氧化物氧还蛋白3（Prdx 3），一种对H2 O2清除很重要的线粒体抗氧化防御酶，减弱了百草枯诱导的认知障碍和A？积累。因此，我们的研究结果表明，增加的风险，AD赋予农药暴露介导的线粒体活性氧（ROS）的产生增加。然而，线粒体ROS介导百草枯暴露引起的认知障碍和A？积累的机制仍不清楚。在本研究中，我们将产生过表达Prdx 3的APP转基因小鼠，包括可诱导过表达Prdx 3的APP转基因小鼠和在特定脑细胞类型如神经元、星形胶质细胞和小胶质细胞中过表达Prdx 3的APP转基因小鼠。然后，我们将研究百草枯暴露对过表达Prdx 3的APP转基因模型和对照APP转基因小鼠的认知和淀粉样蛋白生成的影响。收集的数据将为线粒体ROS介导百草枯诱导的认知障碍和A？积累的详细机制提供有力的证据。本研究中测试的总体假设是：神经元和神经胶质细胞产生的线粒体ROS增加在介导认知障碍和暴露于环境毒素诱导的A？积累中起关键作用。该假设将通过三个具体目标进行检验。目的1，确定百草枯暴露对有或无Prdx 3过表达的AD小鼠模型的认知和A <$积累的长期影响;目的2，确定在百草枯暴露之前或之后Prdx 3过表达对减轻百草枯诱导的认知障碍和A <$积累的影响;目的3，确定Prdx 3在神经元、星形胶质细胞或小胶质细胞中特异性过表达对减轻百草枯诱导的认知障碍和A？积累的影响。 我们的军人在部署期间暴露于各种毒素，如杀虫剂，因此暴露于毒素所带来的AD风险增加是我们军人福祉的严重问题。这项研究中收集的数据将为制定预防和治疗干预措施提供有价值的信息，以降低毒素暴露引起的AD风险，从而使我们的退伍军人受益。