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

描述（由申请人提供）：雌激素被认为在与年龄相关的认知能力下降、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，先前接受激素（雌激素）替代疗法（HRT）的妇女AD发病率降低和认知能力下降有关。此外，临床数据将雌激素缺乏与AD的病因联系起来，但在老年（65岁及以上）绝经后妇女中启动HRT未能改善认知表现。这些发现促使包括我们在内的许多业内人士重新审视雌激素在认知和阿尔茨海默病中的作用，并将目光投向雌激素的直接影响之外的更间接的影响，尽管这些影响可能同样重要。为此，女性和男性的性类固醇水平下降，尽管程度较轻，但由于反馈抑制的丧失，促性腺激素如黄体生成素（LH）的水平会增加。与雌激素一样，黄体生成素也受激素替代疗法的调节，AD患者的血清黄体生成素水平高于与年龄匹配的对照组。此外，最近发表的和初步的数据，包括我们自己的研究，表明LH能够调节认知行为和相关的神经元可塑性标记，存在于大脑中，在海马体中具有最高水平的受体，在AD大脑中增加，并且能够改变淀粉样蛋白-b前体加工。在这一提议中，我们的目标是通过绝经和AD的动物模型来分析雌激素和LH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。具体而言，我们建议测量卵巢切除术后雌性C57/BLJ6和AD转基因小鼠（Tg2576）的认知行为[Morris水迷宫（MWM）任务]、神经元可塑性（通过突触重塑的结构和功能变化来测量）、认知衰退（MWM）和淀粉样蛋白b合成和沉积，然后评估单独或联合药理操纵雌激素和LH水平的“关键窗口”效果。这个系统的分析不仅将解决激素作用在认知中的重要性，而且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。这一建议超越了雌激素的研究，以确定其他hpg轴激素的影响。具体来说，本研究的目的是研究黄体生成素是否是这种损伤的中心介质，是独立的还是与雌激素联合的。这项提议的结果不仅从科学的角度来看很重要，而且可能会立即产生新的治疗方案。

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.