Estrogen Effects on Cholinergic Function in Older Women

描述（由申请人提供）：本申请的主要目的是详细研究雌激素、雌激素拮抗剂和黄体酮对绝经后妇女受脑胆碱能系统影响的认知功能的影响。这些系统对于与年龄相关的认知和行为变化的发展以及阿尔茨海默病等痴呆疾病的症状具有关键的相关性。手术和自然绝经后雌激素水平的变化与认知和行为功能的负面变化有关，这些变化可以通过雌激素治疗来预防。绝经后服用雌激素可降低患阿尔茨海默病的风险。具体来说，这些研究将检查雌激素和相关的性腺类固醇对人脑胆碱能系统的影响，胆碱能系统被认为对注意力、学习、记忆和精神运动表现至关重要。这些研究将利用一种成熟的方法，利用胆碱能（毒蕈碱和烟碱）拮抗剂来探测中枢胆碱能机制的完整性。初步数据表明，短期服用雌激素可以部分保护女性免受胆碱能拮抗剂的负面认知影响。这种作用可能是通过雌激素对中枢胆碱能神经元的营养作用介导的。雌激素对神经生长因子（Nerve Growth Factor， NGF）及其受体等营养因子的表达和活性有实质性影响，从而直接产生神经保护和营养作用。雌激素似乎也具有信号转导调节特性。这些影响在基底前脑的胆碱能神经元中尤其明显。然而，女性现在经常服用可能对抗或改变雌激素作用的药物，如性腺类固醇黄体酮和抗雌激素的他莫昔芬。本研究将探讨雌激素对抗胆碱能诱导的认知变化的急性和慢性影响，雌激素-孕激素联合治疗对胆碱能完整性的影响，以及雌激素拮抗剂他莫昔芬对胆碱能系统的影响。这些研究将提供有关雌激素对胆碱能系统完整性影响的程度和类型的知识，并将有助于了解雌激素在晚年的潜在应用，以维持正常衰老过程中的认知功能，以及预防和/或治疗与年龄相关的认知障碍，如轻度认知障碍和阿尔茨海默病。

DESCRIPTION (provided by applicant): The primary goal of this proposal is to examine in detail the effects of estrogen, estrogen antagonists, and progesterone on cognitive functions that are affected by cholinergic systems of the brain in postmenopausal women. These systems have critical relevance for the development of age-related cognitive and behavioral changes as well as the symptoms of dementing disorders such as Alzheimer's disease. Changes in estrogen levels after surgical and natural menopause are associated with negative changes in cognitive and behavioral functioning, which are preventable by estrogen administration. Administration of estrogen after menopause is associated with a lower risk of Alzheimer's disease. Specifically, these studies will examine the effects of estrogen and related gonadal steroids on the cholinergic system of the human brain that is thought to be critical for attention, learning, memory, and psychomotor performance. These studies will utilize a well-established method for probing the integrity of central cholinergic mechanisms utilizing cholinergic (muscarinic and nicotinic) antagonists. Preliminary data suggest that short-term administration of estrogen partially protects women from the negative cognitive effects of cholinergic antagonists. This effect could be mediated by trophic effects of estrogen on central cholinergic neurons. Estrogen has a substantial effect on the expression and activity of trophic factors such as Nerve Growth Factor (NGF) and its receptors, thereby directly producing neuroprotective and trophic effects. Estrogen also appears to have signal-transduction modulating properties. These effects are observed particularly in cholinergic neurons of the basal forebrain. However, women are now often taking agents, which may antagonize or modify estrogen effects such as the gonadal steroid progesterone and the anti-estrogen tamoxifen. Studies in this proposal will examine the acute vs. chronic effects of estrogen on anti-cholinergic induced cognitive changes, effects of combined estrogen-progesterone treatment on cholinergic integrity, and the effects of the estrogen antagonist tamoxifen on the cholinergic system. These studies will provide knowledge regarding the magnitude and type of effects of estrogen on cholinergic system integrity and will contribute to an understanding of the potential use of estrogen in late life for maintenance of cognitive functioning during normal aging and the prevention and/or treatment of age-related cognitive disorders such as mild cognitive impairment and Alzheimer's disease.