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.

项目总结 人类迟发性阿尔茨海默病(AD)的两个最大主要危险因素是年龄和 载脂蛋白E4基因。虽然衰老和阿尔茨海默病之间的因果关系没有很好的定义，但共同的表型， 例如代谢功能下降和炎症增加，都是强有力的线索。载脂蛋白E基因可能是 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(17αE_2)处理可延长雄性小鼠的寿命和健康指标。而当 女性的寿命没有得到改善，有限的研究试图揭示其他潜在的好处 女性可能会经历17αE2。自17年以来，αE2已被证明作用于全身和神经通路 也与AD病理相关，我们认为17αE2可能构成一种多效性 干预策略。此外，由于载脂蛋白4与年龄相关的表型相关，17αE2可能 优先改善APOE4基因背景下的结果。在这个提案中，我将检验这一假设 17αE2对促进AD的APOE4等位基因引起的衰老表型有保护作用 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APOE3或APOE4的敲入和5xFAD转基因的人APOE3或APOE4的敲入 (EFADs)。目的1测定17-α-E_2对中青年载脂蛋白E_3和载脂蛋白E_4的系统和神经效应 雌性和雄性小鼠，而目标2侧重于17αE2在AD病理发展中的作用，包括 使用E3FAD和E4FAD小鼠的淀粉样β斑块和胶质细胞增多症。我们的初步数据显示， 17αE2在多个结果中的影响差异。我们维持了10个月前的APOE3或APOE4 在没有或存在14.4ppm 17αE2的情况下，对正常饲料中的雄性小鼠进行定向替换，持续20周。 与APOE3相比，ApoE4小鼠表现出衰老的表型，在多个 新陈代谢指标。用17-α-E2治疗后，两种载脂蛋白E基因均有改善，但以 APOE4小鼠对体重、血浆瘦素和肝脏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在外周和神经上都与孕激素效应有关， 与AD风险相关的结果。重要的是，尽管17αE2显著改善了一系列措施 在不同的基因类型中，APOE4基因的影响最大。完成拟议的研究 将进一步强调在评估促进长寿时同时考虑基因和性别的必要性 化合物作为阿尔茨海默病治疗药物。众所周知，年龄在阿尔茨海默病中的重要性，以及 ApoE4，强调使用老年科学和促进长寿的药物干预AD的潜力 发展。