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，暴露于农药等环境毒素会增加患AD的风险。我们最近的研究表明，暴露于农药百草枯可加重AD动物模型的认知功能障碍并增加A？的蓄积，而过氧化还蛋白3(Prdx3)的过度表达可减轻百草枯所致的认知损害和A？的蓄积。因此，我们的结果表明，农药暴露导致的AD风险增加是通过增加线粒体活性氧物种(ROS)的生成来调节的。然而，线粒体ROS在百草枯引起的认知损害和A积聚中的作用机制尚不清楚。在本研究中，我们将产生过表达Prdx3的APP转基因小鼠，包括诱导过表达Prdx3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Prdx3的APP转基因小鼠。然后，我们将研究百草枯暴露对过表达Prdx3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发生的影响。收集到的数据将为线粒体ROS在介导百草枯诱导的认知损害和A积聚中的详细机制提供强有力的证据。本研究验证的总体假说是：神经元和神经胶质细胞产生的线粒体ROS增加，在环境毒素引起的认知损害和A？蓄积中起关键作用。这一假设将通过三个具体目标进行检验。目的1、研究百草枯暴露对AD模型小鼠认知功能和A？蓄积的长期影响；2.研究百草枯暴露前后Prdx3过度表达对减轻百草枯诱导的认知损害和A？蓄积的影响；3.研究Prdx3在神经元、星形胶质细胞或小胶质细胞中的特异性表达对减轻百草枯诱导的认知损害和A？蓄积的影响。我们的服兵役男女在部署期间暴露于各种毒素，如杀虫剂，因此暴露于毒素导致的阿尔茨海默病风险增加是对我们服兵役男女的福祉的严重关切。这项研究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，以减少因毒素暴露而导致的AD风险，从而使我们的退伍军人受益。