Immune Responsiveness, APOE/Gender in Neurodegeneration

描述(申请人提供)：尽管研究方法一直在激烈辩论，但最近出现了一种共识，即阿尔茨海默病(AD)在女性中比在男性中更有可能发展。这种基于性别的差异集中在雌激素方面的研究，特别是女性在衰老过程中缺乏雌激素是阿尔茨海默病神经病理的一个促成因素。众所周知，雌激素在许多层面上对中枢神经系统有益，包括对神经元的直接作用。然而，雌激素也可以改变小胶质细胞的激活和抑制炎症。阿尔茨海默病等神经退行性疾病的特点是脑部炎症是疾病过程的主要组成部分。大脑自身的巨噬细胞，即小胶质细胞，通过释放细胞活性因子，如活性氧(ROS)、细胞因子和蛋白酶，参与这种慢性炎症反应。我们之前发表的数据表明，巨噬细胞免疫反应的水平取决于APOE基因，因此，与不表达APOE4基因的阿尔茨海默病患者相比，表达APOE4基因的阿尔茨海默病患者的激活水平更高。APOE 4基因是众所周知的阿尔茨海默病的“风险”因素，观察到的免疫激活增加与阿尔茨海默病中与APOE4相关的神经变性的严重程度的增加是一致的。在表达人载脂蛋白4的小鼠模型中观察到了与表达人载脂蛋白3的小鼠模型相同的增强巨噬细胞激活的模式。重要的是，在载脂蛋白E介导的免疫功能调节中观察到性别差异，这表明雌激素的存在推翻了载脂蛋白4基因的调节作用。我们这项研究计划的总体目标是在APOE基因和性别等因素的背景下了解疾病中的脑炎症，这些因素调节免疫系统反应的敏感性。因此，在只表达人apoE3蛋白或只表达人apoE4蛋白的小鼠中，我们将研究激素在调节小胶质细胞和腹膜巨噬细胞免疫激活中的作用。

DESCRIPTION (provided by applicant): Although study methodologies have been intensely debated, a consensus has recently emerged that Alzheimer's disease (AD) is more likely to develop in women than in men. This gender-based difference has focused research on estrogen, and specifically, the lack of estrogen during aging in women as a contributing factor to the neuropathology of Alzheimer's disease. Estrogen is known to be beneficial to the CNS at many levels including direct effects on neurons. However, estrogen can also modify microglia activation and suppressing inflammation. Neurodegenerative diseases like Alzheimer's disease feature brain inflammation as a major component of the disease process. The brain's own macrophage, the microglia, participate in this chronic inflammatory response by releasing cytoactive factors such as reactive oxygen species (ROS), cytokines and proteases. Our previously published data demonstrate that the level of macrophage immune responsiveness is dependent on APOE genotype such that a higher level of activation was observed in human Alzheimer's disease patients expressing an APOE4 gene compared to Alzheimer's disease patients that do not express an APOE4 gene. The APOE 4 gene is a well-known "risk" factor for Alzheimer's disease and the observed increase in immune activation is consistent with the increased severity of neurodegeneration associated with APOE4 in Alzheimer's disease. The same pattern of enhanced macrophage activation is observed in mouse models that express human APOE 4 compared to those expressing human APOE3. Importantly, a gender differenced is observed in the APOE-mediated regulation of immune function suggesting that the presence of estrogen overrides the regulatory effects of the APOE4 gene. Our overarching goal of this research program is to understand brain inflammation in disease in the context of factors such as APOE genotype and gender that regulate the sensitivity of the immune system's responsiveness. Thus, we will examine the role of hormones in the regulation of microglial and peritoneal macrophage immune activation in mice expressing only human apoE3 protein or expressing only human apoE4 protein.