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

迟发性阿尔茨海默病（LOAD）占AD病例的95%以上，其病因尚不清楚。 衰老是LOAD的最大风险因素，而APOE β 4被认为是LOAD的主要遗传风险因素。 获得LOAD，女性APOE 104携带者的风险最大。然而，并不是所有的APOE β 4携带者，即使是老年人， 女性携带者，获得AD，这表明其他因素，包括环境暴露必须发挥作用。 臭氧（O3）是一种高活性氧化剂，也是最丰富的城市污染物之一。近期流行病学 研究表明，暴露于高水平的O3与老年人AD发病率的增加有关， APOE β 4携带者比非APOE β 4携带者对O3诱导的记忆衰退更敏感，尽管 没有研究涉及对O3反应的性别差异。在R21项目中，我们测试了O3 使用雄性apoE 4靶标替代（TR）小鼠（仅 由于时间和预算限制，建议使用雄性小鼠）。我们发现，令人惊讶的是， 老年apoE 3（代表携带APOE β 3等位基因的大多数人类群体）雄性小鼠的记忆， 而年长的apoE 4或年轻的apoE 3和apoE 4雄性小鼠则保留6只。与记忆丧失相关的旧apoE 3 雄性小鼠表现出增加的蛋白质氧化修饰（谷胱甘肽化）和神经炎症， 与其他组相比6.另一方面，年老的apoE 4雄性小鼠的体重显著增加， 几种抗氧化酶的表达/活性和减少的蛋白质氧化以及 O3缺乏时的神经炎症6。我们的数据表明，抗氧化能力的提高可能是 老年雄性apoE 4小鼠对O3诱导的记忆丧失的抵抗力增强。我们的数据还表明， 可能会影响敏感性O3诱导的记忆丧失的性别依赖性的方式，就像它的毒性 其他毒物。该R 01将继续我们的R21项目，以进一步测试ApoE β 4的性别依赖性效应， 氧气由于氧化应激在AD的病理生理学和雌激素的血浆水平中起关键作用， 许多抗氧化酶，随着女性年龄的增长而减少，我们的新数据支持的假设是，O3 暴露与衰老和APOE β 4协同作用，以性别依赖的方式导致LOAD， 在女性中促进AD，但在男性中不。我们将在两个特定的目标中测试这一假设，使用apoE 3和apoE 4。 apoE 4 TR小鼠和循环O3暴露方案，模拟人类暴露情况。在目标1中，我们 测试O3暴露在雌性apoE 4 TR小鼠中诱导AD样病理生理学的假设， 他们的男性同行，这是加剧老化。在目标2中，我们将测试恢复 特丁基对苯二酚（TBHQ）的脑抗氧化能力，TBHQ是一种典型的核因子红细胞激活剂 2-相关因子2（Nrf 2），将消除性别-APOE基因型衰老依赖性敏感性O3诱导 神经病理生理学这些研究的结果不仅将揭示LOAD的病因学， 还可能导致制定预防和治疗这种毁灭性疾病的新战略。

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.