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

17 α-雌二醇作为预防阿尔茨海默病发展的潜在保护性治疗剂

• 批准号: 10750423
• 负责人: Cassandra Joan McGill
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750423
• 关键词: Affect; Age; Age Months; Aging; Alleles; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Amyloid; Animals; Apolipoprotein E; Biochemistry; Body Weight; C57BL/6 Mouse; Cognition; Coupled; Data; Development; Disease Progression; Early Onset Alzheimer Disease; Estradiol; Evaluation; Event; Exhibits; Fatty Liver; Female; Genotype; Geroscience; Gliosis; Goals; Health; Human; Immunohistochemistry; Impairment; Inflammation; Inflammatory; Intervention; Knock-in; Knock-in Mouse; Late Onset Alzheimer Disease; Learning; Leptin; Link; Longevity; Measures; Memory; Metabolic; Metabolic dysfunction; Modeling; Mus; Neural Pathways; Obesity; Onset of illness; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Placebos; Plasma; Prevention therapy; Process; Regulation; Risk Factors; Role; Senile Plaques; Testing; Therapeutic; Transgenes; Variant; Wild Type Mouse; age related; aged; apolipoprotein E-3; apolipoprotein E-4; blood glucose regulation; comparison intervention; disease phenotype; drug development; effective therapy; efficacy testing; estrogenic; experience; frailty; healthspan; improved; improved outcome; lipidomics; male; middle age; mouse model; multiple omics; neural; neurogenesis; neuroinflammation; neuronal survival; permissiveness; prevent; programs; screening; sex; stem; targeted treatment; tau aggregation; therapeutic candidate; transcriptomics

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.

项目概要 人类迟发性阿尔茨海默病 (AD) 的两个最大的主要危险因素是衰老和 APOE4 基因型。虽然衰老与 AD 之间的因果关系尚未明确定义，但具有共同的表型， 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）治疗可以延长雄性小鼠的寿命和健康参数。尽管 女性的寿命并没有得到改善，有限的研究试图揭示还有哪些其他潜在的好处 女性可能会经历17αE2。由于 17αE2 已被证明可作用于系统和神经通路 也与 AD 病理学相关，我们认为 17αE2 可能构成多效性 干预策略。此外，由于 APOE4 与年龄相关表型相关，17αE2 可能 优先改善 APOE4 基因型的结果。在这个提案中，我将测试假设 17αE2 可以防止由 APOE4 等位基因引起的衰老表型，从而促进 AD 发展。为了验证这个假设，我将使用两种不同的 AD 风险和早期发病机制小鼠模型： 人 APOE3 或 APOE4 的敲入，以及用 5xFAD 转基因敲入人 APOE3 或 APOE4 （EFAD）。目标 1 确定 17αE2 对中年早期 APOE3 和 APOE4 的系统和神经影响 雌性和雄性小鼠，而 Aim 2 重点关注 17αE2 在 AD 病理发展中的作用，包括 使用 E3FAD 和 E4FAD 小鼠观察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 对多种结果的影响存在差异。我们维持 10 个月大的 APOE3 或 APOE4 在不存在或存在 14.4 ppm 17αE2 的情况下，以正常饮食为目标替代雄性小鼠 20 周。 与 APOE3 相比，APOE4 小鼠表现出衰老表型，在多种方面具有更高的虚弱和损伤 代谢措施。 17αE2 治疗对两种 APOE 基因型均产生了改善，但效果更大 APOE4 小鼠对体重、血浆瘦素和肝脂肪变性等多项指标的影响。这些 数据证实并扩展了先前的发现，即 APOE4 与外周和神经方面的早衰效应有关， 与 AD 风险相关的结果。重要的是，尽管 17αE2 显着改善了一系列措施 在各个基因型中，APOE4 基因型的效果最强。完成拟议的研究 将进一步强调在评估促进长寿时需要考虑基因型和性别 化合物作为 AD 治疗剂。众所周知，年龄在 AD 中的重要性以及早衰效应 APOE4，强调利用老年科学和长寿药物干预 AD 的潜力 发展。