NEUROTROPHIC EFFECTS OF ESTROGENS IN AGING

雌激素已被证明可以调节生长、表型和连接性。 发育中的啮齿动物和人的基底前脑的神经元和 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。最近的报道说 提示雌激素替代绝经后AD的发病率 女性比没有接受这种治疗的女性要低得多。怎么可能？ 雌激素治疗能改变AD的表达吗？因为这个ADC的工作 已经牵涉到疾病的遗传原因，似乎合理 提示雌激素治疗可能保护神经元免受病理性损伤 与AD基因类型相关的变化，或施加营养效应， 撤销与AD相关的更改。这项提案将进一步调查 老年人(或阿尔茨海默病)暴露于神经营养性脑的假说 雌激素的作用导致再生(或保护)作用于 特定脑神经系统的功能活动。如果雌激素 暴露促进轴突生长并重塑神经元连接，它 可能会影响编码重要蛋白的基因的表达 生长和突触发生。我们建议研究雌激素对 包括突触相关蛋白在内的这些蛋白的子集的表达 (Snap-25)、微管相关蛋白2(MAP-2，树突状标志物)、 Tau(微管器和神经原纤维缠结的一个组成部分) 和神经调制素(GAP-43，与神经元生长锥有关)。我们 已经证实GAP-43mRNA的表达对雌激素有反应 发育中的和成人的基底前脑。我们将检测雌激素 老年雌性大鼠三个不同脑区神经元的变化 大脑。(1)经典雌激素靶神经元的神经营养作用：CaN 性腺类固醇恢复纹状体床核的神经元功能 老年雌性大鼠终末和内侧视前区(同前) 在雄性大鼠身上看到的)？雌激素对GAP-43、tau~SNAP-25和MAP2的影响 在表型方面，也将检查已识别的神经元。(2)营养丰富 雌激素对基底前脑胆碱能神经元的影响 老年雌性大鼠治疗可提高胆碱乙酰转移酶活性 和内侧隔-基底前脑系统中的mRNA？我们还将检查 雌激素对胆碱能神经元的直接作用 本地化技术。将这些研究与可能的影响联系起来 AD大脑中的雌激素，我们将在人类基础上进行类似的研究 AD和对照受试者的前脑组织可通过 ADC验尸核心。如果雌激素受体存在于胆碱能 神经元，我们还将评估共定位程度的差异 来自不同遗传背景的阿尔茨海默病患者。 (3)非经典雌激素反应神经元的修复作用 纹状体的种群。尽管几乎没有雌激素受体存在 在纹状体，雌激素治疗增强多巴胺能传递。 这种结构并改善了纹状依赖的运动行为。我们会 检测雌激素对老年大鼠纹状体的营养作用，并与之相关 抗精神病药物对突触后反应的影响 给AD患者用药。这些研究将提供新的信息 在分子和细胞水平上的神经营养作用 老年大脑中的雌激素。这可能有助于我们理解保护性 雌激素的作用。

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.