Estrogen and cognition over the lifespan

描述(由申请人提供)：长期目标是干预，以延缓或防止与不成功老龄化相关的认知衰退，以改善美国老年人的健康和福祉。阿尔茨海默病的发病率预计将急剧增加，其中女性的发病率最高。突触丢失导致记忆损伤，雌激素(E2)促进突触发生和记忆。因此，E2治疗可能会对公共健康产生重大影响。然而，如果在绝经开始几年后进行治疗，E2的疗效就会大大降低，这表明治疗窗口是有限的。有证据表明，雌激素受体(ER)的表达和ER基因多态性与多种激素敏感型疾病有关，包括认知功能减退。我们推测，ER1和ER2的差异表达与E2水平相互作用，导致1)年龄相关性记忆障碍的病因，2)E2介导的突触形成的丧失，以及3)E2治疗窗的关闭。目的1将老化的ER1和ER2基因敲除小鼠与病毒载体相结合来影响ER的表达，并系统地进行行为、分子和电生理测试来验证这一假说。目的2将利用海马区病毒载体在幼年、中年和老年大鼠中增加或减少ER1或ER2，并将使用行为学和分子分析来验证改变ER1/ER2表达比例可以恢复海马功能的假说。AIM 3将利用病毒载体改变ER1或ER2的表达，并将检验ER表达有助于年龄相关的快速E2信号变化的假设。基因敲除小鼠和病毒载体基因传递提供了新的方法来检验ER表达是海马区衰老的一个因素这一假说。总之，这些研究将确定改变ER1或ER2的表达水平是否对年龄相关的记忆下降、E2诱导的突触形成和E2治疗窗口的关闭具有重要意义，并将为开发减缓或防止与衰老和年龄相关疾病相关的认知衰退的治疗方法提供基础。 与公共健康相关：鉴于老年人数量的迅速增长，减少认知能力下降的研究至关重要，其中十分之三的老年人将因年龄和阿尔茨海默氏症而表现出严重的认知能力下降。女性表现出更大的认知衰退风险，占阿尔茨海默病人口的60%以上。这些研究将为干预措施提供科学基础，以避免即将到来的认知障碍老年人浪潮。

DESCRIPTION (provided by applicant): The long range goal is intervention to delay or prevent cognitive decline associated with unsuccessful aging, in order to improve the health and well-being of older Americans. The incidence of Alzheimer's disease is projected to increase dramatically, with the greatest prevalence in women. Synaptic loss contributes to memory impairments and estrogen (E2) promotes synaptogenesis and memory. Thus, E2 treatment could have a major impact on public health. However, the efficacy of E2 is greatly reduced if therapy occurs several years after the onset of menopause, suggesting a temporally limited therapeutic window. Evidence indicates estrogen receptor (ER) expression and ER polymorphisms contribute to a variety of hormone sensitive diseases, including cognitive decline. We hypothesize that differential expression of ER1 and ER2 interacts with the level of E2 to contribute to 1) the etiology of age-related memory deficits, 2) loss of E2 mediated synaptogenesis, and 3) the closing of the E2 therapeutic window. Aim 1 will combine aging ER1 and ER2 knockout mice with viral vectors to influence ER expression and systematically perform behavioral, molecular, and electrophysiological assays to test the hypothesis. Aim 2 will employ hippocampal viral delivery vectors to increase or decrease ER1 or ER2 in young, middle-age, and aged rats, and will use behavioral and molecular assays to test the hypothesis that shifting the ratio of ER1/ER2 expression rejuvenates hippocampal function. Aim 3 will employ viral vectors to alter the expression of ER1 or ER2, and will test the hypothesis that ER expression contributes to age-related changes in rapid E2 signaling. Knockout mice and viral vector gene delivery provide novel approaches to test the hypothesis that ER expression is a contributing factor for hippocampal aging. Together, these studies will determine whether altering the level of ER1 or ER2 expression is important for age-related memory decline, E2-induced synaptogenesis, and closing of the E2 therapeutic window, and will provide the groundwork for development of therapies to slow or prevent cognitive decline associated with aging and age-related diseases. PUBLIC HEALTH RELEVANCE: Research to reduce cognitive decline is crucial, given the burgeoning number of elderly, in which 3 in 10 will display serious cognitive decline due to age and Alzheimer's disease. Women exhibit greater risk for cognitive decline and comprise greater than 60% of the Alzheimer population. These studies will provide a scientific foundation for interventions to avert the impending wave of cognitively impaired seniors.