Ozone, apoE4, aging, and Alzheimer's disease

臭氧、apoE4、衰老和阿尔茨海默病

基本信息

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
项目类别：
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&apos s Disease Animal Model Animals Apolipoprotein E Area Brain Breathing Child Code Data Dementia Dendritic Spines Development Early Onset Familial Alzheimer&apos 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

项目摘要

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（由申请人提供）：迟发性（散发性）阿尔茨海默氏病 (AD) 是一种与衰老相关的神经退行性疾病，其病因尚不清楚。载脂蛋白 E (apoE) 是一种主要的脂质转运蛋白，存在三种亚型（E2、E2、E2）。 E3 和 E4) 在人类中由 3 个不同的等位基因 ϵ2、ϵ3 和 ϵ4 编码。除年龄外，APOE ϵ4 是 AD 的主要遗传风险因素，尽管其潜在机制在很大程度上仍不清楚，但即使在老年，apoE4 的单独表达也不足以引起 AD，这表明包括环境因素在内的其他因素也有影响。臭氧 (O3) 是一种高反应性气体，是最丰富的城市污染物之一，超过 30% 的美国人口生活在臭氧水平不健康的地区。尽管 O3 传统上被认为是一种肺部毒物，但新的证据表明，吸入 O3 还会导致呼吸系统以外的其他组织/器官发生氧化应激，包括 O3 表现出类似 AD 的病理。我们的初步研究进一步表明，循环 O3 暴露（一种模拟人类暴露的情况）会加速 APP/PS1 小鼠（一种成熟的动物）的记忆丧失。我们还发现，O3 暴露会导致 APP/PS1 小鼠的皮质和海马氧化应激和神经细胞死亡，但数据表明，尽管 O3 本身可能不会导致 AD。，它可能会增加遗传易感人群对 AD 的易感性，因为氧化应激对 AD 发病机制有重要影响，并随着年龄的增长而增加，而且 apoE4 小鼠对氧化应激表现出更高的敏感性，因此我们提供了帮助。 O3 暴露与遗传风险因素 apoE4 和衰老产生协同作用，导致迟发性 AD 的发展，我们将使用人类 apoE4 和 apoE3（代表大多数携带 APOE ϵ3 基因的人群）来检验我们的假设。在 Aim 1 中，我们将测试周期性 O3 暴露是否会加速 apoE4 TR 小鼠的记忆丧失以及衰老是否会进一步恶化 O3 效应。 2，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细胞死亡更敏感，以及衰老是否进一步增加这种敏感性。这些研究的结果不仅将为我们提供新的线索。 AD 的病因学，同时也为研究 O3 或其他环境危险因素、apoE4 与衰老在迟发性 AD 发展过程中的相互作用奠定了基础。这些结果将在该领域产生重大影响并进一步引领。开发预防和治疗 AD 的新策略。