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: 8698294
• 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/8698294
• 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）： 阿尔茨海默氏病（AD）是影响数百万人的最常见痴呆症。尽管大多数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（例如农药）会增加发展AD的风险。我们最近表明，暴露于农药paraquat加剧了认知障碍并增加了AD动物模型中的积累，并且过氧氧蛋白3（PRDX3）的过表达是一种线粒体抗氧化剂防御酶，这对H2O2去除很重要，对H2O2去除，对H2O2的去除，降低了副标题的认知和累积的累积和A累积。因此，我们的结果表明，通过增加线粒体活性氧（ROS）的产生增加，由农药暴露的AD风险增加是介导的。然而，线粒体ROS在介导认知障碍和由帕拉Quat暴露引起的积累中的机制尚不清楚。在这项研究中，我们将生成具有PRDX3过度表达的APP转基因小鼠，包括具有PRDX3和APP转基因小鼠的APP转基因小鼠，在特定的脑细胞类型（如神经元，星形胶质细胞和小胶质细胞）中具有PRDX3过表达的App转基因小鼠。然后，我们将研究PRDX3过表达和控制App转基因小鼠的APP转基因模型中帕拉素quat暴露对认知和淀粉样生成的影响。收集的数据将提供有力的证据，证明线粒体ROS的详细机制在介导paraquat诱导的认知障碍和积累中。在这项研究中检验的总体假设是：神经元和神经胶质细胞增加线粒体ROS的产生在介导认知障碍和暴露于环境毒素中引起的积累中起关键作用。该假设将通过三个特定目的进行检验。目的1，确定帕拉quat暴露对具有或没有PRDX3过表达的AD小鼠模型中认知和A积累的长期影响； AIM 2，确定prdx3在暴露之前或之后的过表达对衰减帕拉Quat诱导的认知障碍和A积累的影响；目的3，确定PRDX3过表达在神经元，星形胶质细胞或小胶质细胞中的影响对衰减paraquat诱导的认知障碍和积累的影响。我们的兵役男人和女性在部署过程中暴露于各种毒素，例如农药，因此暴露于毒素的AD风险增加是我们兵役男人和女人的福祉的严重关注。这项研究中收集的数据将提供有价值的信息，以开发预防和治疗性干预措施，以降低毒素暴露的AD风险，从而使我们的退伍军人受益。