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.

项目摘要 人类晚期发作阿尔茨海默氏病（AD）的两个最大的主要危险因素是衰老， APOE4基因型。尽管衰老与AD之间的因果关系尚未很好地定义，但共享表型，但 例如，代谢功能降低和影响力增加，是强力铅。 APOE基因型可能是 通过调节衰老过程与AD表型相关。发现NIA干预测试计划 17α-雌二醇（17αE2）的治疗可以增加雄性小鼠的寿命和健康参数。尽管 女性的寿命没有改善，有限的研究试图发现其他潜在的好处 女性可能会经历17αe2。由于已显示17αE2对全身和神经途径作用 也与AD病理学有关，我们建议17αE2可能构成多效性 干预策略。此外，由于APOE4与年龄相关的表型有关，因此17αE2可能 在APOE4基因型的背景下优先改善结果。在此提案中，我将检验假设 17αE2可以防止促进AD的APOE4捕获引起的衰老表型 发展。为了检验这一假设，我将使用两种不同的AD风险和早期发病机理的小鼠模型： 敲入人ApoE3或apoE4，并用5xFAD转基因敲入人ApoE3或ApoE4 （efads）。 AIM 1确定17αE2对APOE3和APOE4早期中年的系统和神经效应 雌性和雄性小鼠，而AIM 2则侧重于17αE2在AD病理发展中的作用，包括 使用E3FAD和E4FAD小鼠，淀粉样蛋白β斑块和神经病。我们指示基因型的初步数据 17αE2对多个结果的影响差异。我们维护了10个月大的APOE3或APOE4 在不存在或存在14.4 ppm17αe2的情况下，靶向替换雄性小鼠在正常食物上20周。 与APOE3相比，APOE4小鼠暴露了老化的表型，多个 代谢测量。用17αE2处理的两种APOE基因型都得到了改善，但更大 APOE4小鼠对包括体重，血浆瘦素和肝脂肪变性在内的多种措施的影响。这些 数据确认并扩展了先前的发现，即ApoE4与外围和中性效应相关， 与AD风险相关的结果。重要的是，尽管17αE2显着改善了一系列测量 在整个基因型中，它显示了APOE4基因型的强大作用。拟议研究的完成 在评估寿命促进时，将进一步强调需要考虑基因型和性别的需求 化合物作为广告疗法。 AD中年龄的重要性，以及后代的作用 APOE4，突出显示使用Geroscience和使用长寿药物干预AD的潜力 发展。