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

促性腺激素参与认知和阿尔茨海默病：治疗意义

• 批准号: 7507090
• 负责人: Gemma Casadesus
• 金额: $ 28.97万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7507090
• 关键词: Acetates; Acute; Address; Affect; Age; Age-associated memory impairment; Aging; Agonist; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anabolism; Andropause; Animal Model; Animals; Aromatase; Behavior; Brain; Cessation of life; Cholesterol; Chromosome Pairing; Classification; Clinical Data; Cognition; Cognitive; Cognitive deficits; Cytochrome P450; Data; Dementia; Deposition; Development; Disease Progression; Disease susceptibility; Down Syndrome; Effectiveness; Elderly; Elements; Estrogen Replacement Therapy; Estrogen Replacements; Estrogens; Etiology; Event; Feedback; Female; Gender; Gene Expression; General Population; Goals; Gonadal Steroid Hormones; Gonadal structure; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; High Prevalence; Hippocampus (Brain); Hormonal; Hormone replacement therapy; Hormones; Impaired cognition; Impairment; In Vitro; Incidence; Indium; Individual; LH Receptors; Laboratories; Lead; Learning; Leuprolide Acetate; Life; Light; Link; Literature; Luteinizing Hormone; Measures; Mediator of activation protein; Memory; Menopause; Modeling; Molecular; Mus; Neuronal Dysfunction; Neuronal Plasticity; Neurons; Numbers; Onset of illness; Outcome; Output; Ovariectomy; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Performance; Personal Satisfaction; Play; Population; Postmenopause; Predisposition; Process; Protein Precursors; Public Health; Publishing; Rate; Reporting; Risk; Rodent; Role; Saline; Serum; Signal Transduction; Steroid biosynthesis; Steroids; Stroke; Structure; Synapses; Synaptic plasticity; Testing; Tg2576; Therapeutic; Therapeutic Intervention; Thinking; Time; Transgenic Mice; Transgenic Organisms; Treatment Protocols; Woman; Women' s Health; Work; age related; aged; base; cognitive change; cognitive function; critical developmental period; density; genetic regulatory protein; hypothalamic pituitary gonadal axis; improved; lead acetate; men; mitochondrial membrane; morris water maze; mortality; mouse model; novel therapeutics; prevent; protective effect; protein expression; receptor; receptor expression; reproductive hormone; research study; steroid hormone; synaptic function

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.

描述（由申请人提供）：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）的发病机制中起重要作用。流行病学证据表明，以前接受激素（雌激素）替代疗法（HRT）的女性AD发病率降低，认知能力下降。此外，临床数据显示雌激素缺乏与AD的病因相关，但在绝经后老年妇女（65岁及以上）中开始HRT未能改善认知能力。这些发现导致该领域的许多人，包括我们，重新审视雌激素在认知和AD中的作用，并超越雌激素的直接影响，看到更间接的影响，尽管可能同样重要。为此，女性和男性的性类固醇水平下降，尽管程度较低，但通过失去反馈抑制导致促性腺激素如促黄体激素（LH）增加。LH和雌激素一样，受HRT调节，AD患者血清LH水平高于年龄匹配的对照组。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志物，存在于大脑中，在海马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蛋白前体加工。在这个建议中，我们的目标是解剖激素的贡献和相互作用的雌激素和LH对认知，突触可塑性，AD发病机制使用动物模型的更年期和AD。具体来说，我们建议测量认知行为[Morris水迷宫（MWM）任务]，通过突触重塑中的结构和功能变化测量的神经元可塑性，和认知能力下降（MWM）以及淀粉样蛋白-b的合成和沉积，然后评估“临界窗口”的作用。雌激素和LH水平的药理学操作的功效，无论是单独或组合。这一系统分析将不仅解决认知激素作用的重要性，但也将开始解剖雌激素和LH的个人贡献，以及这些方面是如何受到绝经后HRT的时间。公共卫生关系：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。这项建议超越了雌激素的研究，以确定其他HPG轴激素的影响。具体而言，这一机构的工作的目的是调查促黄体生成素是否是一个中央调解人，这种损害，独立或与雌激素。该提案的结果不仅从科学角度来看很重要，而且可能导致立即的新治疗方案。