Ozone, apoE4, aging, and Alzheimer's disease

臭氧、apoE4、衰老和阿尔茨海默病

• 批准号: 8741923
• 负责人: RUI-MING LIU
• 金额: $ 18.38万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8741923
• 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

DESCRIPTION (provided by applicant): 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 ϵ2, ϵ3, and ϵ4. Both epidemiology and animal studies indicate that, beside age, APOE ϵ4 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 ϵ3 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.

描述（由适用提供）：尚不清楚与衰老相关的神经退行性疾病的晚发（零星）阿尔茨海默氏病（AD）的原因。载脂蛋白E（APOE）是人类三种同工型（E2，E3和E4）中存在的主要脂质转运蛋白，由3个不同的等位基因ϵ2，ϵ3和ϵ4编码。流行病学和动物研究都表明，除了年龄以外，ApoE ϵ4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弹性的。然而，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这种遗传倾向的人群中也在AD的发展中起作用。臭氧（O3）是一种高度反应性的气体，是最丰富的城市污染物之一，尽管传统上认为O3被认为是一种肺有毒物质，但美国居住在美国地区的30％以上的人口，新出现的证据表明，O3吸入还会导致其他组织/呼吸器系统以外的其他组织/组织中的氧化应激和病理变化。有趣的是，据报道，居住在空气污染高水平的城市地区的儿童和年轻人，包括大脑中的O3暴露于广告状病理学。我们的初步研究进一步表明，循环O3暴露，模仿人类暴露的情况，加速了APP/PS1小鼠的记忆丧失，App/PS1小鼠是AD的良好动物模型，对野生型小鼠没有显着影响。我们还表明，O3暴露在APP/PS1小鼠的皮质和海马中诱导氧化应激和神经元细胞死亡。总之，数据表明，尽管仅O3可能不会引起AD，但它可能会增加一般易感人群的敏感性。由于含氧应力对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小鼠对氧化物胁迫的敏感性增加，我们假设O3暴露与遗传风险因素APOE4和衰老协同，从而导致晚期发作AD的发展。我们将使用人类APOE4和APOE3（代表携带ApoE ϵ3基因的大多数人口）的两个特定目标测试我们的假设。在AIM 1中，我们将测试环状O3暴露是否会加速APOE4 TR小鼠的内存损失，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小鼠是否比APOE3 TR小鼠对O3诱导的氧化应激，突触功能障碍和神经元细胞死亡更敏感，并且衰老是否会进一步提高这种敏感性。这些研究的结果不仅将为AD的病因提供新的灯光，还为进一步研究O3或其他环境风险因素（APOE4）的相互作用以及在晚期AD开发中衰老的基础。结果将对该领域产生重大影响，并可能导致预防和治疗AD的新策略的发展。