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：
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
项目类别：
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&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

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.

迟发性（散发性）阿尔茨海默病（AD）是一种与衰老相关的神经退行性疾病，其病因是未知。载脂蛋白 E (apoE) 是一种主要的脂质转运蛋白，以三种亚型（E2、E3 和 E4）存在于体内人类，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 的主要遗传风险因素，尽管其根本机制在很大程度上仍然存在难以捉摸。然而，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在 AD 的发展中发挥着一定的作用。易感人群。臭氧 (O3) 是一种高反应性气体，也是最丰富的城市污染物之一美国超过 30% 的人口生活在 O3 水平不健康的地区。虽然O3是传统上认为 O3 是一种肺部毒物，但新出现的证据表明，吸入 O3 也会导致氧化呼吸系统以外其他组织/器官的应激和病理变化。有趣的是，已经报道称，居住在空气污染（包括 O3）水平较高的城市地区的儿童和年轻人表现出他们的大脑中出现类似 AD 的病变。我们的初步研究进一步表明，循环 O3 暴露，这种情况模拟人类暴露，加速 APP/PS1 小鼠的记忆丧失，APP/PS1 小鼠是一种成熟的 AD 动物模型，对野生型小鼠无显着影响。我们还表明，O3 暴露会诱发氧化应激， APP/PS1 小鼠皮质和海马神经元细胞死亡。综合来看，数据表明，尽管单独使用O3可能不会引起AD，但它可能会增加遗传易感人群对AD的易感性。作为氧化应激对 AD 发病机制有重要影响，并随着年龄的增长而增加，apoE4 小鼠显示对氧化应激的敏感性增加，我们假设 O3 暴露与遗传风险因素具有协同作用 apoE4 和衰老，导致迟发性 AD 的发展。我们将在两个具体方面检验我们的假设目标是使用人类 apoE4 和 apoE3（代表大多数携带 APOE e3 的人群）基因）靶向替代（TR）小鼠模型。在目标 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。在目标 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程度高于apoE3 TR小鼠，以及衰老是否进一步增加了这种敏感性。这些结果研究不仅将为 AD 的病因学提供新的线索，而且为进一步研究奠定基础 O3 或其他环境风险因素、apoE4 与衰老在晚期老年痴呆症发展中的相互作用发病AD。研究结果将在该领域产生重大影响，并可能导致新策略的制定用于预防和治疗AD。