Ozone, apoE4, aging, and Alzheimer's disease

臭氧、apoE4、衰老和阿尔茨海默病

• 批准号: 8621919
• 负责人: RUI-MING LIU
• 金额: $ 22.04万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8621919
• 关键词: APP-PS1; Accounting; Age; Aging; Air Pollutants; Air Pollution; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Animal Model; Animals; Apolipoprotein E; Area; Brain; Breathing; Child; Code; Data; Dementia; Dendritic Spines; Development; Early Onset Familial Alzheimer' s Disease; Elderly; Environmental Risk Factor; Epidemiology; Etiology; Exhibits; Exposure to; Foundations; Free Radicals; Functional disorder; Gases; Gene Mutation; Gene Targeting; Genes; Glutathione; Glutathione Disulfide; Health; Hippocampus (Brain); Human; Investigation; Late Onset Alzheimer Disease; Lead; Learning; Life; Light; Lipid Peroxidation; Lipids; Long-Term Potentiation; Lung; Memory; Memory Loss; Mitochondria; Mus; Neurodegenerative Disorders; Organ; Oxidants; Oxidative Stress; Ozone; Pathogenesis; Pathology; Play; Population; Predisposition; Prevention; Prevention strategy; Production; Protein Isoforms; Proteins; Protocols documentation; Recovery; Reporting; Respiratory System; Role; Synapses; Synaptic Transmission; Testing; Tissues; United States; Wild Type Mouse; age related; air filter; apolipoprotein E-3; apolipoprotein E-4; base; body system; density; effective therapy; experience; exposed human population; genetic risk factor; male; morris water maze; mouse model; neuron loss; novel; novel strategies; object recognition; oxidation; pollutant; public health relevance; synaptic function; toxicant; urban area; young adult

The cause for late-onset (sporadic) Alzheimer's disease (AD), an aging-related neurodegenerative disease, is unknown. Apolipoprotein E (apoE) is a major lipid transporter that exists in three isoforms (E2, E3, and E4) in human, coded by 3 distinct alleles e2, e3, and e4. Both epidemiology and animal studies indicate that, beside age, APOE e4 is a major genetic risk factor for AD, although the underlying mechanism remains largely elusive. Expression of apoE4 alone, even in old ages, however, is insufficient to cause AD, suggesting that other factors including environmental factors also play a role in the development of AD in this genetically predisposed population. Ozone (O3) is a highly reactive gas and one of the most abundant urban pollutants with over 30% of the population in the United States living in areas with unhealthy levels of O3. Although O3 is traditionally considered to be a lung toxicant, emerging evidence indicates that O3 inhalation also causes oxidative stress and pathological changes in other tissues/organs beyond the respiratory system. Interestingly, it has been reported that children and young adults living in urban areas with high levels of air pollution including O3 exhibited AD-like pathology in their brain. Our preliminary studies further show that cyclic O3 exposure, a situation that mimics human exposure, accelerates memory loss in APP/PS1 mice, a well-established animal model of AD, with no significant effect in wild type mice. We also show that O3 exposure induces oxidative stress and neuronal cell death in the cortex and hippocampus of APP/PS1 mice. Together, the data suggest that although O3 alone may not cause AD, it may increase the susceptibility of genetically predisposed population to AD. As oxidative stress contributes importantly to AD pathogenesis and increases with age, and as apoE4 mice show increased sensitivity to oxidative stress, we hypothesize that O3 exposure synergizes with genetic risk factor apoE4 and aging, leading to the development of late-onset AD. We will test our hypothesis in two specific aims using human apoE4 and apoE3 (represents the majority of human population who carry the APOE e3 gene) targeted replacement (TR) mouse models. In Aim 1, we will test whether cyclic O3 exposure accelerates memory loss in apoE4 TR mice and whether aging will further exacerbate O3 effect. In Aim 2, we will test whether apoE4 TR mice are more sensitive to O3-induced oxidative stress, synaptic dysfunction, and neuronal cell death than apoE3 TR mice and whether aging further increases such sensitivity. The results from these studies will not only shed new lights on the etiology of AD but also build a foundation for further investigation of the interactions between O3 or other environmental risk factors, apoE4, and aging in the development of late- onset AD. The results will have major impact in the field and may lead to the development of novel strategies for the prevention and treatment of AD.

迟到（零星）阿尔茨海默氏病（AD）的原因是与衰老有关的神经退行性疾病 未知。载脂蛋白E（APOE）是一种主要的脂质转运蛋白，在三种同工型（E2，E3和E4）中存在 人类，由3个不同的等位基因E2，E3和E4编码。流行病学和动物研究都表明，除了 年龄，APOE E4是AD的主要遗传危险因素，尽管基本机制在很大程度上仍然是 难以捉摸。但是，即使在老年中，仅APOE4的表达也不足以引起AD，这表明 包括环境因素在内的其他因素在遗传上也在AD的发展中起作用 诱人的人口。臭氧（O3）是一种高反应性气体，是最丰富的城市污染物之一 美国超过30％的人口居住在不健康的O3水平。虽然O3是 传统上认为是肺有毒物质，新兴的证据表明O3吸入也会引起氧化性。 呼吸系统以外的其他组织/器官的压力和病理变化。有趣的是，已经 报道说，居住在城市地区的儿童和年轻人，包括O3（O3） 大脑中的广告状病理。我们的初步研究进一步表明，循环O3暴露，这种情况 模仿人类暴露，加速APP/PS1小鼠的记忆力丧失，AD/PS1小鼠是一个公认的AD动物模型， 对野生型小鼠没有显着影响。我们还表明，O3暴露会诱导氧化应激和 APP/PS1小鼠的皮质和海马中的神经元细胞死亡。数据一起表明，虽然 仅O3可能不会引起AD，它可能会增加遗传易感人群对AD的敏感性。作为 氧化应激对AD发病机理有重要贡献，并且随着年龄的增长而增加，并且随着APOE4小鼠的表现 提高对氧化应激的敏感性，我们假设O3暴露与遗传风险因素协同作用 APOE4和衰老，导致晚期广告的发展。我们将在两个特定的两个特定中检验我们的假设 目的使用人类APOE4和APOE3（代表了携带APOE E3的大多数人口 基因）靶向替换（TR）小鼠模型。在AIM 1中，我们将测试循环O3暴露是否加速 APOE4 TR小鼠的记忆丧失以及衰老是否会进一步加剧O3效应。在AIM 2中，我们将测试 APOE4 TR小鼠是否对O3诱导的氧化应激，突触功能障碍和神经元更敏感 细胞死亡比APOE3 TR小鼠以及衰老是否进一步提高了这种敏感性。这些结果 研究不仅会为AD的病因开发新的灯光，而且还为进一步调查奠定了基础 O3或其他环境风险因素（APOE4）之间的相互作用以及晚期发展的衰老 发作广告。结果将对该领域产生重大影响，并可能导致新型策略的发展 用于预防和治疗AD。