Ozone, apoE4, aging, and Alzheimer's disease

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，其原因是 未知载脂蛋白E（apoE）是一种主要的脂质转运蛋白，在大肠杆菌中以三种亚型（E2、E3和E4）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的一个主要遗传危险因素，尽管潜在的机制在很大程度上仍然存在， 难以捉摸然而，即使在老年，apoE 4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的发展中发挥作用， 易感人群。臭氧（O3）是一种高活性气体，是最丰富的城市污染物之一， 美国超过30%的人口生活在O3含量不健康的地区。虽然O3 传统上被认为是一种肺毒物，新的证据表明，O3吸入也会导致氧化 呼吸系统以外的其他组织/器官的应激和病理变化。有趣的是， 报告说，儿童和年轻人生活在城市地区的空气污染水平高，包括O3表现出 他们大脑中的AD样病变我们的初步研究进一步表明，循环O3暴露，一种情况， 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， 对野生型小鼠没有显著影响。我们还表明，O3暴露诱导氧化应激， APP/PS1小鼠皮层和海马神经元细胞死亡。数据显示，尽管 O_3本身可能不引起AD，它可能增加遗传易感人群对AD的易感性。作为 氧化应激在AD发病机制中起重要作用，并随着年龄的增长而增加， 增加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， apoE 4和衰老，导致迟发性AD的发展。我们将在两个具体的实验中验证我们的假设。 目的是使用人apoE 4和apoE 3（代表携带APOE e3的大多数人群 基因）靶向置换（TR）小鼠模型。在目标1中，我们将测试循环O3暴露是否会加速 apoE 4 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 apoE 4 TR小鼠是否对O3诱导的氧化应激、突触功能障碍和神经元损伤更敏感， 与apoE 3 TR小鼠相比，衰老是否进一步增加了这种敏感性。结果从这些 这些研究不仅为AD的病因学研究提供了新的思路，而且为进一步的研究奠定了基础 O3或其他环境危险因素，apoE 4和衰老之间的相互作用，在发展中的晚期- AD发病研究结果将在该领域产生重大影响，并可能导致新战略的发展 用于预防和治疗AD。

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.