Short-term estradiol use in middle-age: implications for female cognitive aging

中年短期使用雌二醇：对女性认知衰老的影响

• 批准号: 8373343
• 负责人: JILL M DANIEL
• 金额: $ 27.77万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373343
• 关键词: Age; Age-associated memory impairment; Aging; Area; Biochemical; Brain; Cell Culture Techniques; Choline O-Acetyltransferase; Cognition; Cognitive; Cognitive aging; Data; Dementia; Estradiol; Estrogen Receptor alpha; Estrogen Therapy; Estrogens; Exposure to; Female; Gene Proteins; Gene Targeting; Genetic Transcription; Goals; Growth Factor; Health; Hippocampus (Brain); Hormones; Impaired cognition; Incidence; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Interferon Gamma Receptor Beta Chain; Intervention; Long-Term Effects; MAP Kinase Gene; Mediating; Memory; Menopausal Symptom; Menopause; Nature; Neurons; Ovarian; Ovary; Pathway interactions; Phosphorylation Site; Population; Proteins; Public Health; Rattus; Reporter Genes; Research; Response Elements; Risk; Signal Pathway; Signal Transduction Pathway; Site; System; Testing; Time; United States; Woman; Women' s Health; aged; aging brain; aging hippocampus; critical period; experience; middle age; prevent; receptor; research study

DESCRIPTION (provided by applicant): Estrogen administration begun during a critical window near menopause is hypothesized to prevent or delay age-associated cognitive decline. However, due to potential health risks women often limit use of estrogen therapy to a few years to treat menopausal symptoms. The long-term consequences for the brain of short-term use of estrogens are unknown. The long-term goal of the research is to determine the consequences for the female brain and for female cognitive aging of short-term exposure to estrogens during middle-age such as that used by women during the menopausal transition. The central hypothesis to be tested is that lasting changes in levels of estrogen receptor alpha (ER¿) and in the insulin-like growth factor-1 (IGF-1) system in the hippocampus resulting from short-term exposure to exogenously administered estradiol in middle-age following the cessation of ovarian function permanently alters the interaction between ER¿ and the IGF-1 system in the hippocampus of the aging female brain resulting in increases in levels of ER¿ target genes and proteins and in enhancement of hippocampus-dependent memory. Guided by preliminary data, this hypothesis will be tested by three specific aims: 1) Determine the nature of the interaction between IGF-1 and ER¿ in hippocampal neurons; 2) Determine the respective contributions of ER¿ and IGF-1 receptors in the ability of short-term estradiol exposure to exert lasting impacts on the hippocampus and on hippocampus-dependent memory; and 3) Determine the extent to which the effects of IGF-1 on the hippocampus and on hippocampus-dependent memory in aged females vary dependent upon previous hormone experience. Experiments under the first aim will use primary hippocampal cell cultures to determine the ability of IGF-1 and its signaling pathways to induce ER¿-mediated transcriptional activity from an estrogen response element driven reporter gene and to induce activation on of specific phosphorylation sites on ER¿. Experiments under the second aim will assess the impact of pharmacological blockage of brain IGF-1 receptors, ER¿, or both on the ability of short-term estradiol exposure in middle-aged ovariectomized rats to exert lasting impacts on ER¿ target genes and associated proteins in the hippocampus and on hippocampus-dependent memory. Experiments under the third aim will determine effects of centrally administered IGF-1 on hippocampus-dependent memory, IGF-1 associated signal transduction pathways, and ER¿ target genes and associated proteins in aged ovariectomized rats that have and have not undergone estradiol exposure during middle-age. This research is expected to have a positive impact on the study of female cognitive aging by providing elucidation of mechanisms by which a relatively short-term exposure to exogenously administered estradiol during a critical period following the cessation of ovarian function exerts lasting impacts on the hippocampus and on cognition. PUBLIC HEALTH RELEVANCE: As the population of the United States ages, increased incidence of age-associated dementias will become a major public health issue. Interventions that could delay the onset of cognitive decline by even one or two years would have a major public health impact. These data will help determine the mechanism by which short- term administration of estrogens near the time of menopause could exert lasting benefits to the cognitive health of women as they age.

描述（由适用提供）：假设在更年期附近的关键窗口开始的雌激素给药以预防或延迟与年龄相关的认知能力下降。但是，由于潜在的健康风险，妇女经常将雌激素疗法的使用限制为几年以治疗绝经症状。短期使用雌激素的长期后果尚不清楚。该研究的长期目标是确定女性大脑的后果以及在中年期间短期暴露于雌激素的女性认知衰老，例如在绝经期间妇女使用的雌激素。要测试的中心假设是，雌激素受体α（ER？）的持久变化以及在海马中的胰岛素样生长因子1（IGF-1）系统中，由于短期暴露于在卵巢中，在卵巢中，在卵巢中，在卵巢中，在卵巢中，雌性脑部的外源性雌二醇的短期暴露导致了卵巢中的雌激素，而卵巢的相互作用是卵巢的互动，而在卵巢中，卵巢的相互作用是在卵巢中的相互作用，而卵巢的相互作用是卵巢的互动，而卵巢的相互作用是igf-f-1导致靶基因和蛋白质水平的增加以及海马依赖性记忆的增强。在初步数据的指导下，该假设将通过三个特定目的进行检验：1）确定海马神经元中IGF-1和ER之间相互作用的性质； 2）确定ER？和IGF-1接收器对短期雌二醇暴露对海马和海马依赖性记忆的持久影响的能力的相对贡献； 3）确定IGF-1对年龄女性的海马和海马依赖性记忆的影响的程度各不取决于先前的激素经验。第一个目标下的实验将使用原发性海马细胞培养物来确定IGF -1及其信号传导途径诱导ER介导的转录活性的能力，从雌激素反应元件驱动的报告基因并诱导ER上的特定磷酸化位点的激活。第二个目标下的实验将评估脑IGF-1受体的药物阻塞，或对中级卵巢大鼠短期雌二醇暴露的能力，对Hippocampus和Hippocampus依赖性依赖性依赖性依赖性蛋白质和相关蛋白产生持久影响。第三个目标下的实验将确定中心施用的IGF-1对海马依赖性记忆，IGF-1相关的信号转移途径以及ER？靶基因和相关蛋白在中年龄衰老的卵巢切除大鼠中的靶基因和相关的蛋白质的影响。预计这项研究将对女性认知衰老的研究产生积极的影响，通过阐明机制，通过这种机制，在停止卵巢功能施加持续的影响时对海马和认知对卵巢功能施加持续的影响后，相对短期暴露于外源性施用的雌二醇。 公共卫生相关性：随着美国年龄的人口，与年龄相关的痴呆症的发病率增加将成为一个主要的公共卫生问题。可能将认知能力下降延迟的干预措施甚至一两年都会产生重大的公共卫生影响。这些数据将有助于确定更年期近期雌激素短期给药的机制，可以随着妇女的年龄认知健康带来持久的好处。