Sex-dependent synergy between O3 exposure, APOE4 e4 genotype, and aging in the onset of Alzheimer's disease

O3 暴露、APOE4 e4 基因型和衰老在阿尔茨海默病发病过程中的性别依赖性协同作用

• 批准号: 10584765
• 负责人: RUI-MING LIU
• 金额: $ 44.14万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584765
• 关键词: Address; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Antioxidants; Brain; Budgets; Complex; Data; Development; Dietary Supplementation; Disease; Disease model; Elderly; Environmental Exposure; Environmental Risk Factor; Estrogens; Etiology; Exhibits; Exposure to; Female; Functional disorder; Genotype; Human; Hydroquinones; Incidence; Late Onset Alzheimer Disease; Memory Loss; Memory impairment; Modification; Molecular; Mus; Oxidants; Oxidative Stress; Ozone; Periodicity; Plasma; Play; Population; Predisposition; Prevention strategy; Proteins; Protocols documentation; Resistance; Risk; Risk Factors; Role; Sex Differences; Testing; Time; Toxic Environmental Substances; Toxic effect; air filter; antioxidant enzyme; apolipoprotein E-3; apolipoprotein E-4; epidemiology study; exposed human population; genetic risk factor; high risk; insight; male; neuroinflammation; neurotoxicity; novel; novel strategies; nuclear factor-erythroid 2; oxidation; ozone exposure; pollutant; response; restoration; sex; synergism; toxicant

The etiology for late-onset Alzheimer’s disease (LOAD), which accounts for >95% of AD cases, is unknown. Aging is the greatest risk factor for LOAD, whereas APOE4 is believed to be a major genetic risk factor in acquiring LOAD, with female APOE4 carriers at the greatest risk. Yet, not all of APOE4 carriers, even older female carriers, acquire AD, suggesting that other factors including environmental exposure must play a role. Ozone (O3) is a highly reactive oxidant and one of the most abundant urban pollutants. Recent epidemiology studies show that exposure to high levels of O3 is associated with an increased incidence of AD in the elderly and that APOE4 carriers are more sensitive to O3-induced memory decline than non-APOE4 carriers are, although no study has addressed sex-differences in response to O3. In an R21 project, we tested the hypothesis that O3 exposure synergies with aging and APOE4 leading to AD, using male apoE4 target replacement (TR) mice (only male mice were proposed due to time and budget limitation). We found, surprisingly, that O3 exposure impaired memory in old apoE3 (represents the majority of human population who carry the APOE3 allele) male mice, while old apoE4 or young apoE3 and apoE4 male mice were spared 6. Associated with memory loss, old apoE3 male mice exhibit increased protein oxidative modifications (glutathionylation) and neuroinflammation, compared to other groups6. Old apoE4 male mice, on the other hand, have significantly increased expression/activities of several antioxidant enzymes and diminished protein oxidation as well as neuroinflammation upon O3 exposure6. Our data suggest that an elevated antioxidant capacity may underlie the increased resistance of old male apoE4 mice to O3-induced memory loss. Our data also suggest that APOE4 may affect the sensitivity to O3-induced memory loss in a sex-dependent manner, just as it does to the toxicities of other toxicants. This R01 will continue our R21 project to further test sex-dependent effects of ApoE4 and O3. As oxidative stress plays a critical role in AD pathophysiology and plasma level of estrogen, an inducer of many antioxidant enzymes, decreases with age in females, our new data-supported hypothesis is that O3 exposure synergizes with aging and APOE4 leading to LOAD in sex-dependent manner, which is to promote AD in females but not in males. We will test this hypothesis in two specific Aims, using apoE3 and apoE4 TR mice and a cyclic O3 exposure protocol, which mimics human exposure scenarios. In Aim 1, we will test the hypothesis that O3 exposure induces AD-like pathophysiology in female apoE4 TR mice compared to their male counterparts and this is exacerbated by aging. In Aim 2, we will test the hypothesis that restoration of brain antioxidant capacity with tert-butyl hydroquinone (TBHQ), a canonical activator of nuclear factor erythroid 2-related factor 2 (Nrf2), will eliminate sex-APOE genotype-aging-dependent sensitivity to O3-induced neuropathophysiology. The results from these studies will not only shed new light on the etiology of LOAD but may also lead to the development of new strategies for the prevention and treatment of this devastating disease.

尚不清楚占AD病例的95％的晚期阿尔茨海默氏病（负载）的病因（负载）尚不清楚。 衰老是负载的最大危险因素，而APOE4被认为是主要的遗传危险因素 获得负载，并带有最大风险的女性APOE4载体。但是，并不是所有的Apoe4载体，甚至更老 女性承运人收购广告，表明包括环境暴露在内的其他因素必须发挥作用。 臭氧（O3）是一种高反应性氧化物，也是最丰富的城市污染物之一。最近的流行病学 研究表明，暴露于高水平的O3与较老的AD事件增加有关，并且 与非APOE4载体相比，ApoE4载体对O3诱导的记忆下降更敏感，但是 没有研究针对O3解决性别差异。在R21项目中，我们检验了O3的假设 使用雄性APOE4目标置换（TR）小鼠，与衰老和APOE4的暴露协同作用（仅 由于时间和预算限制，提出了雄性小鼠。令人惊讶的是，O3暴露受损 旧apoe3中的记忆（代表大多数携带apoe3等位基因的人口）雄性小鼠， 旧的ApoE4或Young ApoE3和ApoE4雄性小鼠被保留6。 雄性小鼠暴露于增加蛋白质氧化物的修饰（谷胱甘肽化）和神经炎症， 与其他组相比6。另一方面，旧的Apoe4雄性小鼠已经显着增加 几种抗氧化剂酶的表达/活性和蛋白质氧化减少的表达/活性以及 O3暴露时神经炎症6。我们的数据表明，抗氧化能力升高可能是 旧雄性APOE4小鼠对O3诱导的记忆丧失的阻力增加。我们的数据还表明apoe4 可能以性别依赖性的方式影响O3诱导的记忆丧失的敏感性，就像对毒性一样 其他有毒物质。该R01将继续我们的R21项目，以进一步测试APOE4和 O3。由于氧化应激在AD病理生理学和雌激素的血浆水平中起关键作用，这是一种诱导剂 许多抗氧化剂酶，随着女性的年龄而降低，我们的新数据支持的假设是O3 暴露与衰老和apoe4协同作用，导致性别依赖性的方式，即 在女性中促进广告，但不在男性中促进广告。我们将使用APOE3和 APOE4 TR小鼠和环状O3暴露方案，该方案模仿了人类暴露的情况。在AIM 1中，我们将 检验以下假设，即O3暴露与与 他们的男性同行，这会因衰老而加剧。在AIM 2中，我们将检验以下假设 脑抗氧化能力，用TERT叔丁基氢醌（TBHQ），核因子红系的规范激活剂 与2个相关因子2（NRF2），将消除对O3诱导的性别基因型的依赖性敏感性 神经病理生理学。这些研究的结果不仅会对负载的病因介绍 还可能导致发展这种毁灭性疾病的新策略。