PERIMENOPAUSE AND GLIAL INFLAMMATORY RESPONSES THAT INTERACT WITH NEURON AGING

阿尔茨海默病（Alzheimer disease，AD）涉及多个层面的炎症过程。因为卵巢类固醇显示 AD的激素治疗（HT）具有多种抗炎活性，可能涉及激活炎症通路 在更年期过渡期，荷尔蒙不足逐渐出现。我们提出啮齿动物模型 分析易患AD的脑区的炎症变化，重点是 在衰老的Sprague-Dawley大鼠身上。3xTg-AD小鼠模型将用于检查特定假设 关于衰老过程中炎症与人类家族性AD的关系。这些模型将被检查， 根据E2 +循环P4的KEEPS临床模型，对HT的反应性。我们将检查E2-P4 在炎症和神经营养作用中对小胶质细胞-星形胶质细胞相互作用的影响。 特定目的1：人围绝经期和绝经期大鼠和小鼠模型中的炎症特征 阶段（动物核心B）。1.1.海马和海马神经元炎症基因表达及生物信息学分析 来自不同绝经阶段的衰老大鼠和小鼠的大脑皮层（Analytic Core）。1.2.体外 脑膜炎周围炎性变化的建模，使用源自 围绝经期大鼠1.3.从围绝经期大鼠培养的神经胶质细胞的生物能量学（项目1）。 具体目标2：使用神经胶质细胞- 神经元共培养物。2.1.炎症基因在胶质细胞介导的神经元支持中的作用。2.2作用 雌激素受体（ER α：ER| 3）调节脑膜周围胶质细胞炎性表型。星形胶质细胞 老年大鼠缺乏神经营养支持，其中一个因素是雌激素受体比例改变 ERa：ERp（试点数据）。2.3.孕激素受体在调节脑膜周围胶质细胞中的作用 炎症变化，重点是Pgmrcl（试点数据）。2.4.神经胶质细胞NOS 2在神经元凋亡中的作用 线粒体功能障碍（与项目1）。2.5.肥胖-炎症相互作用（与项目3）。 具体目标3：围脑膜炎HT对脑细胞炎症的影响。根据E2的KEEPS模型 + 在围月经周期阶段，将给予循环P4大鼠和3xTg-AD小鼠HT。3.1. 炎症基因表达和生物信息学（分析核心）。3.2.炎症的体外模型 变化，使用老化大鼠大脑皮层的初级胶质细胞。3.3.神经胶质培养物的生物能量学（与项目 1）。 相关性（见说明）： 我们的主要目标是建立围绝经期过渡期的动物模型， 对卵巢类固醇敏感。研究结果与优化激素治疗以防止 正常年龄相关认知功能减退、多发性梗塞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