Estrogen and cognition over the lifespan

描述（由申请人提供）：长期目标是干预延迟或预防与不成功衰老相关的认知衰退，以改善美国老年人的健康和福祉。预计阿尔茨海默病的发病率将急剧增加，其中妇女发病率最高。突触丢失导致记忆障碍，雌激素（E2）促进突触发生和记忆。因此，E2治疗可能对公共卫生产生重大影响。然而，如果在绝经后数年进行治疗，E2的疗效会大大降低，这表明治疗窗口时间有限。有证据表明，雌激素受体（ER）的表达和ER多态性有助于多种激素敏感性疾病，包括认知能力下降。我们假设ER 1和ER 2的差异表达与E2水平相互作用，导致1）年龄相关性记忆缺陷的病因学，2）E2介导的突触发生的丧失，以及3）E2治疗窗的关闭。目的1将联合收割机将衰老的ER 1和ER 2基因敲除小鼠与病毒载体相结合，以影响ER表达，并系统地进行行为、分子和电生理检测来验证这一假设。目的2将采用海马病毒载体增加或减少年轻，中年和老年大鼠的ER 1或ER 2，并将使用行为和分子测定来测试改变ER 1/ER 2表达比例恢复海马功能的假设。目的3将采用病毒载体来改变ER 1或ER 2的表达，并将测试ER表达有助于快速E2信号传导中的年龄相关变化的假设。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表达是海马老化的一个促成因素的假设。总之，这些研究将确定改变ER 1或ER 2表达水平是否对年龄相关的记忆衰退、E2诱导的突触发生和E2治疗窗口的关闭很重要，并将为开发减缓或预防与衰老和年龄相关疾病相关的认知衰退的疗法提供基础。

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.