PERIMENOPAUSE AND GLIAL INFLAMMATORY RESPONSES THAT INTERACT WITH NEURON AGING

阿尔茨海默病(AD)涉及多个层面的炎症过程。因为卵巢类固醇显示 许多ANFI-炎症活动，激素治疗(HT)在AD中可能涉及激活的炎症通路 在更年期过渡期间，荷尔蒙缺乏逐渐出现。我们提出了啮齿动物模型 围绝经期阶段分析易患AD的大脑区域的炎症变化，重点 关于衰老的Spraogue-Dawley大鼠。3xTg-AD小鼠模型将被用来检验特定的假设 关于衰老期间的炎症与人类家族性阿尔茨海默病的关系。我们将对这些型号进行检查 对羟色胺的反应性，根据Keep临床模型的E2+周期P4。我们将检查E2-P4 脑损伤和神经营养效应对小胶质细胞-星形胶质细胞相互作用的影响。 具体目标1：人类围绝经期和绝经期大鼠和小鼠模型的炎性变化 阶段(动物核心B)。1.1.大鼠海马炎性基因表达及生物信息学分析 不同绝经阶段老龄大鼠和小鼠的大脑皮层(Analytic Core)。1.2.离体 使用来源于以下来源的原代胶质细胞培养建立围绝经期炎症变化的模型 围绝经期大鼠。1.3.围绝经期大鼠神经胶质细胞培养的生物能量学(附项目1)。 特定目标2：围绝经期炎症变化中的神经退行性机制，使用神经胶质细胞- 神经元共培养。2.1.炎症基因在神经胶质细胞介导的神经元支持中的作用。2.2、角色 雌激素受体(ERA：ER|3)调节围绝经期神经胶质细胞炎症表型。星形胶质细胞来自 衰老大鼠缺乏神经营养支持，其中一个因素是雌激素受体的比例改变。 时代：企业资源规划(试点数据)。2.3.孕激素受体在围绝经期神经胶质细胞调节中的作用 炎症性变化，重点是PgmrCL(试点数据)。2.4.神经胶质细胞N0S2在神经元中的作用 线粒体功能障碍(项目1)。2.5.肥胖与感染的相互作用(与项目3)。 具体目标3：围绝经期高血压对脑细胞炎症的影响。遵循E2的Keep模式 +周期P4、大鼠和3xTg-AD小鼠在围绝经期周期阶段给予羟色胺。3.1. 炎性基因表达和生物信息学(Analytic Core)。3.2.体外炎症模型的建立 变化，使用老化大鼠大脑皮层的原代胶质细胞。3.3.神经胶质细胞培养的生物能量学(附项目 1)。 相关性(请参阅说明)： 我们的主要目标是开发围绝经期转变的动物模型来分析脑细胞 对卵巢类固醇的敏感性。研究结果与优化荷尔蒙疗法以预防 正常年龄相关性认知功能减退、多发性梗死性痴呆和阿尔茨海默病

Alzheimer disease (AD) involves infiammatory processes at many levels. Because ovarian steroids show many anfi-infiammatory activities, hormone therapy (HT) in AD may involve inflammatory pathways activated during the menopause transitions when hormonal deficits emerge progressively. We propose rodent models of perimenopausal stages to analyze inflammatory changes in brain regions vulnerable to AD, with a focus on aging Sprague-Dawley rats. The 3xTg-AD mouse model will be used to examine specific hypothesis about relationships of inflammation during aging to human familial AD. These models will be examined for responsiveness to HT, according to the KEEPS clinical model of E2 + cyclic P4. We will examine E2-P4 effects on microglial-astrocyte interacfions in infiammafion and in neurotrophic effects. Specific Aim 1: Infiammatory profile in rat and mouse models of human perimenopause and menopause stages (Animal Core B). 1.1. Inflammatory gene expression and bioinformafic analysis in hippocampus and cerebral cortex of aging rats and mice from different menopausal stages (Analytic Core). 1.2. In vitro modeling of perimenopausal inflammatory changes, using primary glial cultures originated from perimenopausal rats. 1.3. Bioenergefics of glia cultured from perimenopausal rats (with Project 1). Specific Aim 2: Neurodegenerative mechanisms in perimenopausal infiammatory changes, using glial- neuronal co-cultures. 2.1. Role of infiammatory genes in glial-mediated neuronal support. 2.2, Role of estrogen receptors (ERa:ER|3) in regulating perimenopausal glial inflammatory phenotypes. Astrocytes from aging rats are deficient in neurotrophic support, in which one factor is altered ratio of estrogen receptors ERa:ERp (pilot data). 2.3. Role of progesterone receptors (PR) in regulafing perimenopausal glial infiammatory changes, with a focus on Pgmrcl (pilot data). 2.4. Role of glial N0S2 in neuronal mitochondria dysfunction (with Project 1). 2.5. Obesity-infiammation interactions (with Project 3). Specific Aim 3: Effects of perimenopausal HT on brain cell infiammation. Following the KEEPS model of E2 + cyclic P4, rats and 3xTg-AD mice will be given HT during perimenopausal cycling stages. 3.1. Infiammatory gene expression and bioinformafics (Analytic Core). 3.2. In vitro models of infiammatory changes, using primary glial from aging rat cerebral cortex. 3.3. Bioenergefics of glial cultures (with Project 1). RELEVANCE (See instmctions): Our primary goal is to develop animal models for the perimenopause transition to analyze brain cell sensitivity to ovarian steroids. Findings are relevant to optimization of hormone therapy to protect against normal age-related cognitive decline, multi-infarct demenfia and Alzheimers Diease