Estrogen and cognition over the lifespan

描述（由申请人提供）：长期目标是通过干预延缓或预防与不成功的衰老相关的认知能力下降，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，其中妇女发病率最高。突触丧失导致记忆障碍，雌激素（E2）促进突触形成和记忆。因此，E2治疗可能对公众健康产生重大影响。然而，如果在绝经后几年才开始治疗，E2的疗效会大大降低，这表明治疗时间有限。有证据表明，雌激素受体（ER）表达和ER多态性与多种激素敏感性疾病有关，包括认知能力下降。我们假设ER1和ER2的差异表达与E2水平相互作用，有助于1)年龄相关记忆缺陷的病因学，2)E2介导的突触发生的丧失，以及3)E2治疗窗口的关闭。目的1将衰老的ER1和ER2基因敲除小鼠与病毒载体结合，以影响ER表达，并系统地进行行为、分子和电生理分析来验证这一假设。目的2将利用海马病毒传递载体在年轻、中年和老年大鼠中增加或减少ER1或ER2，并将使用行为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设。目的3将采用病毒载体来改变ER1或ER2的表达，并将验证ER表达有助于快速E2信号的年龄相关变化的假设。敲除小鼠和病毒载体基因传递为验证内质网表达是海马衰老的一个促进因素的假设提供了新的方法。总之，这些研究将确定ER1或ER2表达水平的改变是否对年龄相关的记忆衰退、E2诱导的突触发生和E2治疗窗口的关闭具有重要意义，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.