A Mouse Model of Inflammation in Alzheimer's Disease

描述（由申请人提供）：本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产生。为了实现这一目标，我们将使用我们开发的新型AD小鼠模型。这些小鼠表现出ad样病理，包括：（1)淀粉样蛋白沉积，（2)体突神经元室中天然小鼠tau蛋白过度磷酸化和聚集，(3)神经元丢失，4）严重认知缺陷和5）神经血管单元损伤。通过将表达突变人类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，产生双基因hAPP/NOS2-/-小鼠，产生ad样疾病表型。通过在免疫反应中降低小鼠体内的NO水平，这些小鼠表现出全谱的ad样病理。来自APPSw/NOS2-/-小鼠的初步数据显示出全谱AD样病理，表明炎症基因谱与AD患者大脑中的免疫谱高度相似。在双基因小鼠和AD大脑中，观察到一个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）或下调反应（获得性失活）的基因。我们的首要假设是免疫状态在阿尔茨海默病的疾病过程中起着因果作用。我们假设，常驻免疫细胞在免疫特性上经历了复杂的变化，以响应在疾病的整个生命周期中变化的A¿。我们还假设这些免疫变化改变了特定AD病理水平或改变了疾病进展。我们将通过以下途径来研究大脑的免疫状态：1)利用免疫激活状态的特定候选标记物（经典、替代和获得性失活）识别大脑先天免疫系统的变化，作为AD病理水平和疾病进展的功能；2)通过使用将改变激活谱的干预措施来研究先天免疫激活状态在疾病发病机制中的因果作用；3)研究TNFa的细胞毒性潜能。它是AD中最有可能损伤神经元的免疫调节细胞因子。公共卫生启示：该项目将研究大脑先天免疫状态在产生与慢性神经退行性疾病（如阿尔茨海默病）相关的神经病理学中的作用。

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.