A Mouse Model of Inflammation in Alzheimer's Disease

描述(申请人提供)：这项研究项目的首要目标是了解大脑中的先天免疫系统如何参与阿尔茨海默病的发生。为了实现这一目标，我们将使用我们开发的AD的新型小鼠模型。这些小鼠表现出类似AD的病理，包括(1)淀粉样沉积，(2)体内tau蛋白过度磷酸化和聚集，(3)神经元丢失，4)强健的认知缺陷和5)神经血管单位损伤。这种AD样疾病的表型是通过将表达突变的人APP的小鼠与缺乏功能性一氧化氮合酶2(NOS2)基因的小鼠杂交产生的，以产生双基因HAPP/NOS2-/-小鼠。通过在免疫反应中降低小鼠体内的NO水平，使其与人类的水平更接近，这些小鼠表达了全谱的AD样病理。来自APPSw/NOS2-/-小鼠的初步数据显示，全谱的AD样病理表明，炎症基因图谱与人类AD患者大脑的免疫图谱高度相似。在BigGen小鼠和AD脑中，都观察到一种复杂的免疫激活状态，包括编码经典促炎因子的基因和编码抗炎因子、修复因子(替代激活)或下调调节反应(获得性失活)的基因。我们的主要假设是，免疫状态在AD的疾病过程中起着因果作用。我们假设，在疾病的整个生命周期中，居民免疫细胞对A？的反应经历了复杂的免疫属性变化。我们还假设，这些免疫变化改变了特定AD病理的水平或改变了疾病的进展。我们将通过以下方式研究大脑的免疫状态：1)使用免疫激活状态(经典、替代和获得性失活)的特定候选标记物，确定大脑固有免疫系统作为AD病理水平和疾病进展的函数的变化；2)通过修改激活模式的干预措施，研究固有免疫激活状态在疾病发病机制中的因果作用；3)研究TNFa的细胞毒性潜力，TNFa是最有可能在AD中损害神经元的免疫调节细胞因子。公共卫生评论：这个项目将研究大脑的先天免疫状态在产生与阿尔茨海默病等慢性神经退行性疾病相关的神经病理中所起的作用。

DESCRIPTION (provided by applicant): The overarching goal of this research project is to understand how the innate immune system in the brain participates in the generation of Alzheimer's disease. To accomplish this goal, we will use novel mouse models of AD that we have developed. These mice show AD-like pathology including (1) amyloid deposits, (2) hyperphosphorylated and aggregated native mouse tau in the somatodendritic neuronal compartment, (3) neuronal loss, 4) robust cognitive deficits and 5) neurovascular unit damage. The AD-like disease phenotype was generated by crossing mice that express mutated human APP with mice that lack a functional nitric oxide synthase 2 (NOS2) gene to produce a bigenic hAPP/NOS2-/- mouse. By reducing NO levels in mice during an immune response to those levels more equivalent in human, these mice express a full spectrum of AD-like pathology. Preliminary data from the APPSw/NOS2-/- mice that show a full spectrum of AD-like pathology demonstrate an inflammatory gene profile highly reminiscent of the immune profile in brains of humans with AD. In both bigenic mice and AD brain, a complex immune activation state is observed that includes genes that code for classical pro-inflammatory factors and genes that code for anti-inflammatory factors, repair factors (alternative activation) or down-regulatory responses (acquired deactivation). Our overarching hypothesis is that the immune state plays a causal role in the disease process in AD. We hypothesize that resident immune cells undergo complex changes in immune properties in response to A¿ that vary throughout the life cycle of the disease. We also hypothesize that these immune changes alter the levels of specific AD pathology or alter disease progression. We will study the brain's immune status by 1) identifying changes in the brain's innate immune system as a function of the level of AD pathology and of disease progression using specific candidate markers of immune activation states (classical, alternative and acquired deactivation), 2) investigating the causal role of the innate immune activation state in disease pathogenesis by using interventions that will modify activation profiles and 3) investigating the cytotoxic potential of TNFa, the most likely immune-regulated cytokine to damage neurons in AD. PUBLIC HEALTH REVELANCE: This project will examine the role of the brain's innate immune state in generating the neuropathology associated with chronic neurodegenerative diseases such as Alzheimer's disease.