NEUROTROPHIC EFFECTS OF ESTROGENS IN AGING

雌激素已被证明可以调节生长，表型和连接 发育中的啮齿动物和人类基底前脑的神经元， 海马体。 这种改变神经元形态和连接的能力 保留在成人大脑的某些区域 最近的报告 提示雌激素替代绝经后AD的发病率 妇女的死亡率比未接受这种治疗的妇女低得多。 什么样子 雌激素治疗改变AD的表达？ 由于这个ADC的工作 暗示了这种疾病的遗传原因，似乎有理由 提示雌激素治疗可能保护神经元免受病理性损伤， 与AD基因型相关的变化，或产生营养效应， 与AD相关的更改。 这份提案将进一步调查 假设老年人（或AD）大脑暴露于神经营养素 雌激素的作用导致再生（或保护）作用， 特定大脑神经系统的功能活动。 如果雌激素 暴露促进神经突生长和重塑神经元连接， 可能会影响编码蛋白质的基因的表达， 生长和突触发生。 我们建议检查雌激素对 表达包括突触相关蛋白在内的这些蛋白的子集 （SNAP-25），微管相关蛋白2（MAP-2，树突状标记物）， Tau（微管器和神经元缠结的组成部分） 和神经调节素（GAP-43，与神经生长锥相关）。 我们 已经确定GAP-43 mRNA表达对雌激素有反应， 无论是发育中的还是成年的基底前脑。 我们会检查雌激素 对老年雌性大鼠三个不同脑区神经元的影响 个脑袋(1)经典雌激素靶向神经元的神经营养作用：可以 性腺类固醇恢复纹状体床核的神经元功能 老年雌性大鼠的终肌和内侧视前区（如前所述 在雄性大鼠中观察到）？ 雌激素对GAP-43、tau~ SNAP-25和MAP 2的影响 也将检查表型鉴定的神经元。(2)营养 雌激素对基底前脑胆碱能神经元的影响 治疗老年雌性大鼠增强胆碱乙酰转移酶活性 内侧隔-基底前脑系统mRNA的表达水平？ 我们亦会研究 雌激素对胆碱能神经元的直接作用 本地化技术。 将这些研究与 雌激素在AD大脑中的作用，我们将在人类基础上进行类似的研究。 来自AD和对照受试者的前脑脑组织可通过 ADC尸检核心 如果雌激素受体存在于 神经元，我们还将评估共定位程度的差异 与不同遗传背景相关的AD患者。 (3)非经典雌激素反应性神经元的修复作用 纹状体的人口。 尽管雌激素受体很少 在纹状体，雌激素治疗增强多巴胺能传递， 这种结构，并改善纹状体依赖的运动行为。 我们将 检查老年大鼠纹状体中雌激素的营养作用，并将这些 抗精神病药物对突触后反应的影响通常 给AD患者服用。 这些研究将提供新的信息 在分子和细胞水平上， 老年大脑中的雌激素 这可能有助于我们理解保护性 雌激素的影响。

Estrogens have been shown to modulate growth, phenotype, and connectivity of neurons of the developing rodent and human basal forebrain and hippocampus. This ability to alter neuronal morphology and connectivity is retained in certain regions of the adult brain. Recent reports have suggested that the incidence of AD in estrogen replaced postmenopausal women is much lower than in women not given this treatment. How might estrogen treatment alter the expression of AD? Since the work of this ADC has implicated genetic causes of the disease, it seems reasonable to suggest that estrogen treatment might protect neurons from pathological changes associated with the AD genotypes, or exert trophic effects which reverse the AD-related changes. This proposal will further investigate the hypothesis that exposure of the aged (or AD) brain to neurotrophic effects of estrogens results in regenerative (or protective) effects on the functional activity of particular brain neuronal systems. If estrogen exposure promotes neurite outgrowth and remodels neuronal connectivity, it might influence the expression of genes encoding proteins important in growth and synaptogenesis. We propose to examine estrogens effects on expression of a subset of these including Synapse Associated Protein (SNAP-25), Microtubule Associated Protein 2 (MAP-2, a dendritic marker), Tau (a component of the microtubule apparatus and neurofibrillary tangles) and neuromodulin (GAP-43, associated with the neuronal growth cone). We have established that GAP-43 mRNA expression is responsive to estrogen in both the developing and adult basal forebrain. We will examine estrogen's effects on neurons in three different regions of the aged female rat brain. (1) Neurotrophic Effects in Classical Estrogen Target Neurons: Can gonadal steroids restore neuronal function in the bed nucleus of the stria terminalis and medial preoptic area of the aged female rat (as previously seen in male rats)? Estrogen's effects on GAP-43, tau~ SNAP-25, and MAP2 in phenotypically identified neurons will also be examined. (2) Trophic Effects of Estrogen on Basal Forebrain Cholinergic Neurons: Does estrogen treatment of aged female rats enhance choline acetytransferase activity and mRNA in medial septal-basal forebrain system? We will also examine the direct effects of estrogen on cholinergic neurons using co- localization techniques. To relate these studies to possible effects of estrogens in AD brain, we will carry out similar studies in human basal forebrain brain tissue from AD and control subjects available through the ADC autopsy core. If estrogen receptors are present in cholinergic neurons, we will also assess differences in the degree of co-localization from individuals with AD associated with differing genetic backgrounds. (3) Restorative effects in non-classical estrogen responsive neuronal populations of the striatum. Although few estrogen receptors are present in the striatum, estrogen treatment enhances dopaminergic transmission in this structure and improves striatally-dependent motor behaviors. We will examine trophic effects of estrogen in aged rat striatum, and relate these effects to postsynaptic responses to antipsychotic drugs commonly administered to AD patients. These studies will provide new information at the molecular and cellular level about neurotrophic effects of estrogens in the aged brain. This may aid our understanding of protective effects of estrogens.