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

主要研究者/项目负责人（最后，第一，中间）：Casadesus，Gemma 项目摘要 雌激素被认为在与年龄相关的认知能力下降、神经元功能减退、 可塑性，以及阿尔茨海默病（AD）的发病机制。流行病学证据 与AD发病率降低和先前暴露于 激素（雌激素）替代疗法（HRT）。此外，临床数据与雌激素相关 缺乏AD病因，但在绝经后老年人（年龄65岁及以上）中开始HRT 女性的认知能力没有提高。这些发现导致了该领域的许多人， 包括我们在内，重新审视雌激素在认知和AD中的作用， 从雌激素的直接作用到更间接的，尽管可能同样重要的作用。本 最后，女性和男性的性类固醇水平下降，尽管程度较低，导致 通过失去反馈抑制，促性腺激素如促黄体激素（LH）增加。 LH与雌激素一样，也受HRT调节，AD患者血清LH水平较高 与年龄匹配的对照组相比。此外，最近公布的初步数据，包括 我们自己的研究表明，LH能够调节认知行为， 神经可塑性标记物，存在于大脑中，在大脑中具有最高水平的受体。 海马，在AD大脑中增加，并且能够改变淀粉样蛋白 前驱体处理在这个提议中，我们的目标是剖析荷尔蒙的贡献， 雌激素和LH对认知、突触可塑性和AD发病机制的相互作用 绝经和AD动物模型。具体来说，我们建议测量认知行为， [Morris水迷宫（MWM）任务]，通过结构和功能测量的神经元可塑性 突触重塑、认知能力下降（MWM）和淀粉样蛋白合成的变化， 卵巢切除后雌性C57/BLJ 6和AD转基因小鼠（Tg 2576）中的沉积， 然后，评估A的影响。 关键窗口 药理学操作的有效性 雌激素和LH水平，单独或组合。这一系统分析不仅 解决荷尔蒙作用在认知中的重要性，但也将开始剖析 雌激素和LH的个体贡献以及这些方面如何受到后 HRT的绝经时间。 项目描述第6页

Principal Investigator/Program Director (Last, first, middle): Casadesus, Gemma Project Summary 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-¿ 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-¿ 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. Project Description Page 6