Ozone, apoE4, aging, and Alzheimer's disease

描述（由申请人提供）：迟发性（散发性）阿尔茨海默病（AD）是一种与年龄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体，存在于人类的三种亚型（E2， E3和E4）中，由三个不同的等位基因ϵ2， ϵ3和ϵ4编码。流行病学和动物研究都表明，除了年龄之外，APOE ϵ4是AD的主要遗传风险因素，尽管其潜在的机制仍然难以捉摸。然而，即使在老年人中，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这一遗传易感性人群中AD的发展中起作用。臭氧（O3）是一种高活性气体，也是最丰富的城市污染物之一，美国超过30%的人口生活在臭氧水平不健康的地区。虽然O3传统上被认为是一种肺毒性物质，但新出现的证据表明，吸入O3也会导致呼吸系统以外的其他组织/器官的氧化应激和病理变化。有趣的是，据报道，生活在包括臭氧在内的高水平空气污染的城市地区的儿童和年轻人的大脑中表现出ad样病理。我们的初步研究进一步表明，模拟人类暴露的循环O3暴露加速了AD动物模型APP/PS1小鼠的记忆丧失，而对野生型小鼠无显著影响。我们还发现O3暴露可诱导APP/PS1小鼠皮层和海马的氧化应激和神经元细胞死亡。综上所述，这些数据表明，虽然O3单独可能不会导致阿尔茨海默病，但它可能会增加遗传易感性人群对阿尔茨海默病的易感性。由于氧化应激在AD发病中起着重要作用，并随着年龄的增长而增加，而apoE4小鼠对氧化应激的敏感性增加，我们假设O3暴露与遗传风险因子apoE4和衰老协同作用，导致晚发性AD的发生。我们将使用人类apoE4和apoE3（代表携带APOE ϵ3基因的大多数人类群体）靶向替代（TR）小鼠模型在两个特定目标中验证我们的假设。在Aim 1中，我们将测试循环暴露O3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O3效应。在Aim 2中，我们将测试apoE4 TR小鼠是否比apoE3 TR小鼠对氧诱导的氧化应激、突触功能障碍和神经元细胞死亡更敏感，以及衰老是否会进一步增加这种敏感性。这些研究结果不仅为阿尔茨海默病的病因学研究提供了新的思路，而且为进一步研究O3或其他环境危险因素、apoE4和衰老在晚发型阿尔茨海默病发展中的相互作用奠定了基础。该结果将在该领域产生重大影响，并可能导致开发预防和治疗阿尔茨海默病的新策略。

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.