Gonadotropin involvement in cognition and Alzheimer's disease: Therapeutic Implic

说明(申请人提供)：雌激素被认为在与年龄相关的认知衰退、神经元可塑性以及阿尔茨海默病(AD)的发病机制中发挥重要作用。流行病学证据表明，在以前接受激素(雌激素)替代疗法(HRT)的女性中，AD的发病率下降与认知能力下降有关。此外，临床数据表明雌激素缺乏与AD的病因有关，然而在老年(65岁及以上)绝经后妇女中启动HRT并不能改善认知能力。这些发现促使包括我们在内的该领域的许多人重新研究雌激素在认知和阿尔茨海默病中的作用，并将目光从雌激素的直接影响转向更间接的影响，尽管可能同样重要。为此，女性和男性性激素水平的下降，尽管程度较小，但会通过失去反馈抑制而导致促性腺激素(如促黄体生成素)的增加。与雌激素一样，黄体生成素也受到激素替代疗法的调节，与年龄匹配的对照组相比，AD患者的血清黄体生成素水平更高。此外，最近公布的初步数据，包括我们自己的研究，表明黄体生成素能够调节认知行为和相关的神经元可塑性标记物，存在于大脑中，在海马区具有最高水平的受体，在AD大脑中增加，并能够改变淀粉样蛋白-b前体的处理。在这个方案中，我们的目标是利用更年期和AD的动物模型来剖析雌激素和黄体生成素在认知、突触可塑性和AD发病机制中的激素贡献和相互作用。具体地说，我们建议测量卵巢切除后雌性C57/BLJ6和AD转基因小鼠(Tg2576)的认知行为[Morris水迷宫(MWM)任务]，通过突触重构的结构和功能变化来衡量神经元的可塑性，以及认知衰退(MWM)和淀粉样蛋白-b的合成和沉积，然后评估单独或联合使用药物操纵雌激素和黄体生成素水平的“关键窗口”的效果。这一系统的分析不仅将讨论荷尔蒙在认知中作用的重要性，还将开始剖析雌激素和黄体生成素的个体贡献，以及这些方面如何受到绝经后HRT时间的影响。公共卫生相关性：绝经后HPG轴激素的变化，特别是雌激素，与老年人的认知障碍和AD的发展密切相关。这一建议超越了对雌激素的研究，以确定其他HPG轴激素的影响。具体地说，这项工作的目标是调查促黄体激素是否是这种损害的中心媒介，独立地或与雌激素一起。该提案的结果不仅从科学角度来看很重要，而且可能立即导致新的治疗方案。

DESCRIPTION (provided by applicant): Estrogen is thought to play an important role in age-related cognitive decline, neuronal plasticity, as well as the pathogenesis of Alzheimer disease (AD). Epidemiological evidence linked decreased incidence of AD and cognitive decline in women previously exposed to hormone (estrogen) replacement therapy (HRT). Further, clinical data correlates estrogen deficiency to the etiology of AD, yet initiating HRT in elderly (age 65 and over) post-menopausal women failed to improve cognitive performance. These findings have led many in the field, including us, to re-examine the role of estrogen in cognition and AD and to look beyond the direct effects of estrogen to more indirect, though perhaps no less important, effects. To this end, declining levels of sex steroids in women and men, albeit to a lesser degree, result in increases in gonadotropins such as luteinizing hormone (LH) through loss of feedback inhibition. LH, like estrogen, is modulated by HRT and serum levels of LH are higher in AD patients compared to aged-matched controls. Moreover, recent published and preliminary data, including our own studies, show that LH is capable of modulating cognitive behavior and associated neuronal plasticity markers, is present in the brain, has the highest levels of receptors in the hippocampus, is increased in the AD brain, and is capable of altering amyloid-b protein precursor processing. In this proposal, our goal is to dissect the hormonal contributions and interactions of estrogen and LH on cognition, synaptic plasticity, and AD pathogenesis using animal models of menopause and AD. Specifically, we propose to measure cognitive behavior [Morris Water Maze (MWM) task], neuronal plasticity as measured by structural and functional changes in synaptic remodeling, and cognitive decline (MWM) and amyloid-b synthesis and deposition in female C57/BLJ6 and AD transgenic mice (Tg2576) after ovariectomy and thereafter assess the effect of a "critical window" of efficacy of pharmacological manipulation of estrogen and LH levels, either singly or in combination. This systematic analysis will not only address the importance of hormonal action in cognition but will also begin to dissect the individual contributions of estrogen and LH and how these aspects are affected by the post-menopausal timing of HRT. PUBLIC HEALTH RELEVANCE: Postmenopausal changes in HPG-axis hormones, in particular estrogen, is tightly linked to cognitive impairment in older individuals and development of AD. This proposal trascends beyond the study of estrogen to determine the influence of other HPG-axis hormones. Specifically, the objective of this body of work is to investigate whether luteinizing hormone is a central mediator of such impairment, independently or in conjunction with estrogen. Outcomes of the proposal are not only important from a scientific perspective but could lead to immediate novel therapeutic regimens.