Gonadotropin in cognition and Alzheimer's disease: Therapeutic Implications

促性腺激素在认知和阿尔茨海默氏病中的作用：治疗意义

• 批准号: 8103837
• 负责人: Gemma Casadesus
• 金额: $ 25.99万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103837
• 关键词: 21 year old; 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; Clinical Data; Cognition; Cognitive; Cognitive deficits; Data; Dementia; Deposition; Development; Disease Progression; Disease susceptibility; Down Syndrome; Effectiveness; Elderly; Elements; Epidemiology; 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; Health; 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; Onset of illness; Outcome; Output; Ovariectomy; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Performance; Play; Population; Postmenopause; Predisposition; Process; Protein Precursors; Publishing; Regimen; Reporting; Rodent; Role; Saline; Serum; Signal Transduction; Steroid biosynthesis; Steroids; Stroke; Structure; Synapses; Synaptic plasticity; Testing; Tg2576; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; Woman; Women' s Health; age related; aged; base; cognitive change; cognitive enhancement; cognitive function; critical period; density; genetic regulatory protein; high risk; hypothalamic pituitary gonadal axis; improved; 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下降，神经元可塑性以及阿尔茨海默氏病（AD）的发病机理中起着重要作用。流行病学证据将AD的发病率降低和先前暴露于激素（雌激素）替代疗法（HRT）的女性的认知下降联系在一起。此外，临床数据将雌激素缺乏症与AD的病因相关，但在绝经后妇女的老年人（65岁及以上）启动HRT未能提高认知表现。这些发现导致了包括我们在内的领域中的许多人重新检查雌激素在认知和AD中的作用，并超越了雌激素对更间接的直接影响，尽管也许同样重要，但也是如此。为此，尽管程度较低，但男性和男性的性类固醇水平下降，导致促性腺激素的增加，例如通过失去反馈抑制，例如黄体生成激素（LH）。与雌激素一样，LH受到HRT的调节，与年龄匹配的对照相比，AD患者的血清水平更高。此外，最近发布和初步数据（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物，存在于大脑中，在AD大脑中具有最高水平的受体受体，并且能够改变淀粉样蛋白-B蛋白质前体处理。在此提案中，我们的目标是使用更年期和AD的动物模型剖析雌激素和LH对认知，突触可塑性和AD发病机理的激素贡献和相互作用。具体而言，我们建议测量认知行为[Morris Water Maze（MWM）任务]，通过突触重塑的结构和功能变化来衡量的神经元可塑性，以及认知能力下降（MWM）以及淀粉样蛋白-B的合成和女性C57/BLJ6和Ad Transententententent of Transgenic Mite（Tg2576）的效果（TG2576）的效果（雌激素和LH水平的药理学操纵的功效，无论是单独的还是组合。这种系统的分析不仅将解决荷尔蒙作用在认知中的重要性，而且还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HRT的绝经后时间的影响。公共卫生相关性：HPG-轴激素的绝经后变化，尤其是雌激素，与老年人的认知障碍与AD的发展密切相关。该提议超出了雌激素的研究，以确定其他HPG轴激素的影响。具体而言，这项工作的目的是研究黄体生成激素是独立或与雌激素结合的这种损害的中心介体。该提案的结果不仅从科学角度来看很重要，而且可能导致直接的新型治疗方案。