17 alpha-estradiol as a potential protective therapeutic against development of Alzheimer's disease

项目摘要 人类中迟发性阿尔茨海默病（AD）的两个最大的主要风险因素是衰老和阿尔茨海默病。 APOE 4基因型。虽然衰老和AD之间的因果关系还没有很好的定义，但共有的表型， 例如代谢功能下降和炎症增加，是强有力的线索。APOE基因型可能是 通过调节衰老过程与AD表型相关。NIA干预测试计划发现， 17α-雌二醇（17αE2）治疗可增加雄性小鼠的寿命和健康参数。而 女性的寿命没有延长，有限的研究试图揭示其他潜在的好处 女性可能患有17αE2。由于17αE2已被证明作用于全身和神经通路， 我们认为17αE2可能是一种多效性蛋白， 干预策略。此外，由于APOE 4与年龄相关的表型有关，17αE2可能 优先改善APOE 4基因型背景下的结局。在这份提案中，我将检验 17αE2可以防止由促进AD的APOE 4等位基因引起的衰老表型， 发展为了验证这一假设，我将使用两种不同的AD风险和早期发病机制的小鼠模型： 人APOE 3或APOE 4的敲入，和用5xFAD转基因敲入人APOE 3或APOE 4 （EFAD）。目的1探讨17αE2对中老年人APOE 3和APOE 4的全身和神经效应 雌性和雄性小鼠，而Aim 2关注17αE2在AD病理学发展中的作用，包括 β淀粉样蛋白斑块和神经胶质增生。我们的初步数据表明基因型 17αE2对多种结局的影响差异。我们维持了10个月大的APOE 3或APOE 4 在不存在或存在14.4 ppm 17αE2的情况下，靶向替代雄性小鼠进食正常食物20周。 与APOE 3相比，APOE 4小鼠表现出衰老的表型，在多个器官中具有更高的虚弱和损伤。 代谢指标用17αE2治疗使两种APOE基因型均得到改善，但 在APOE 4小鼠中对包括体重、血浆瘦素和肝脂肪变性在内的几种测量的影响。这些 数据证实并扩展了先前的发现，即APOE 4与外周和神经的早衰效应有关， 与AD风险相关的结果。重要的是，尽管17αE2显著改善了一系列指标， 在所有基因型中，它在APOE 4基因型中显示出最强的影响。完成拟议的研究 将进一步强调，在评估促进长寿的基因型时， 化合物作为AD治疗剂。众所周知，年龄在AD中的重要性，沿着 APOE 4，强调使用老年科学和长寿促进药物干预AD的潜力 发展

PROJECT SUMMARY The two largest primary risk factors for late onset Alzheimer’s Disease (AD) in humans are aging and the APOE4 genotype. While the causal relationship between aging and AD is not well defined, shared phenotypes, such as decreased metabolic function and increased inflammation, are strong leads. APOE genotype may be linked to AD phenotype through the regulation of aging processes. The NIA Interventions Testing Program found that 17α-estradiol (17αE2) treatment can increase the lifespan and health parameters of male mice. While lifespan was not improved in females, limited studies have sought to uncover what other potential benefits females may experience with 17αE2. Since 17αE2 has been shown to act upon systemic and neural pathways that have also been associated with AD pathology, we propose that 17αE2 may constitute a pleiotropic intervention strategy. Further, because APOE4 is associated with age-related phenotypes, 17αE2 may preferentially improve outcomes in the context of APOE4 genotype. In this proposal, I will test the hypothesis that 17αE2 protects against aging phenotypes caused by the APOE4 allele that promote AD development. To test this hypothesis, I will use two different mouse models of AD risk and early pathogenesis: knock-in of human APOE3 or APOE4, and knock-in of human APOE3 or APOE4 with 5xFAD transgenes (EFADs). Aim 1 determines the systemic and neural effects of 17αE2 on APOE3 and APOE4 early middle-aged female and male mice, while Aim 2 focuses on the role of 17αE2 in the development of AD pathology, including amyloid beta plaques and gliosis, using E3FAD and E4FAD mice. Our preliminary data indicate genotype differences in the impact of 17αE2 across multiple outcomes. We maintained 10-month-old APOE3 or APOE4 targeted replacement male mice on normal chow in the absence or presence of 14.4 ppm 17αE2 for 20 weeks. APOE4 mice exhibited an aged phenotype compared to APOE3, with higher frailty and impairments in multiple metabolic measures. Treatment with 17αE2 yielded improvements in both APOE genotypes but with greater effects in APOE4 mice on several measures including body weight, plasma leptin, and hepatic steatosis. These data confirm and extend prior findings that APOE4 is linked to progeroid effects both peripherally and neurally, outcomes associated with AD risk. Importantly, although 17αE2 significantly improved a range of measures across genotypes, it shows the strongest effects in the APOE4 genotype. Completion of the proposed studies will further emphasize the need to consider both genotype and sex when assessing longevity-promoting compounds as AD therapeutics. The well-known importance of age in AD, along with the progeroid effect of APOE4, highlight the potential to use geroscience and longevity-promoting drugs to intervene in AD development.