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)是一种主要的脂类转运蛋白，它以三种亚型(E_2、E_3和E_4)存在于 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，载脂蛋白E e4是AD的主要遗传风险因素，尽管潜在的机制在很大程度上仍然 难以捉摸。然而，即使在老年人中，仅有apoE4的表达也不足以导致AD，这表明 包括环境因素在内的其他因素也在阿尔茨海默病的发生中发挥了作用 易受感染的人群。臭氧是一种活性很强的气体，也是城市污染物中含量最多的一种， 美国超过30%的人口生活在臭氧水平不健康的地区。尽管臭氧是 传统上被认为是一种肺部毒物，新的证据表明，吸入臭氧也会导致氧化 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，它一直是 报道称，生活在包括臭氧在内的空气污染水平较高的城市地区的儿童和年轻人表现出 在他们的大脑中有广告样的病理。我们的初步研究进一步表明，周期性的臭氧暴露，这种情况 模拟人类暴露，加速APP/PS1小鼠的记忆丧失，APP/PS1小鼠是公认的AD动物模型， 对野生型小鼠无明显影响。我们还表明，接触臭氧会诱导氧化应激，并 APP/PS1小鼠大脑皮层和海马神经细胞死亡。总而言之，数据表明，尽管 单独使用臭氧可能不会引起AD，它可能会增加遗传易感人群对AD的易感性。AS 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，apoE4小鼠的研究表明 对氧化应激的敏感性增加，我们假设接触臭氧与遗传风险因素有协同作用 载脂蛋白E4和衰老，导致迟发性AD的发展。我们将通过两个具体的例子来检验我们的假设 AIMS使用人类apoE4和apoE3(代表携带apoE E3的大多数人类人口 基因)靶向替换(Tr)小鼠模型。在目标1中，我们将测试周期性臭氧暴露是否会加速 ApoE4 tr小鼠的记忆丧失以及衰老是否会进一步加剧臭氧效应。在目标2中，我们将测试 载脂蛋白E4受体小鼠是否对臭氧诱导的氧化应激、突触功能障碍和神经元更敏感 与apoE3 tr小鼠相比，细胞死亡以及衰老是否会进一步增加这种敏感性。这些研究的结果 研究不仅将为AD的病因提供新的线索，而且还将为进一步研究奠定基础 臭氧或其他环境风险因素、载脂蛋白E4与衰老在晚期发育中的相互作用 公元一开始。这一结果将在该领域产生重大影响，并可能导致新战略的发展 用于防治阿尔茨海默病。

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.