IL-1 mediated activation of innate immunity underlies Alzheimer plaque clearance

描述(申请人提供)：神经炎症是中枢神经系统(CNS)对伤害性刺激的局部组织反应，其特征是胶质反应、细胞因子和趋化因子的诱导以及血管通透性。它还可能涉及外周免疫细胞的招募。在这一反应中的一个关键角色是促炎细胞因子白介素1？IL-1在急性中枢神经系统损伤或损伤后迅速在小胶质细胞中诱导，并可能在持续或重复的有害刺激存在的条件下慢性过度表达，例如在阿尔茨海默病(AD)等神经退行性疾病中。出于这个原因，IL-1一直被认为会促进神经退行性变。本实验室以前的工作是利用大脑持续产生IL-1的新模型和AD的小鼠模型来研究IL-1和AD发病机制之间的联系。该模型显示了空间和时间控制的IL-1依赖的神经炎性反应，显著减少了APPswe/PS1阿尔茨海默病小鼠的斑块病理。重要的是，初步工作发现淀粉样蛋白周围的小胶质细胞数量增加-？IL-1过度表达动物的斑块。为了更好地表征内源性IL-1在AD发病机制中的作用，我们将量化APP/PS1小鼠斑块发展过程中内源性IL-1的表达。为了巩固IL-1的慢性表达和淀粉样蛋白清除之间的联系，进一步的研究将使用转基因和病毒载体的方法来实现IL-1信号的持续上调，并分析各种AD的病理特征。此外，我们假设IL-1通过诱导先天免疫反应来诱导小胶质细胞介导的斑块清除。在我们的模型中，MCP-1的显著升高和淀粉样斑块周围小胶质细胞数量的增加支持了这一点。为了研究外周单核细胞募集是否是导致观察到的细胞增加的原因，我们的目标是在持续的IL-1？表情。类似的方法将被用来确定骨髓来源的小胶质细胞是否在观察到的斑块清除中发挥作用。我们提出的研究将有助于阐明脑部炎症在神经退行性疾病中的作用。这一点至关重要，因为炎症已被提议作为这些疾病的治疗靶点。阿尔茨海默氏症是我们老龄化社会的一个重大公共卫生挑战，为更好地了解它的发展过程而采取的步骤可能会导致新的治疗方法或方法来预防疾病。

DESCRIPTION (provided by applicant): Neuroinflammation is a local tissue response to injurious stimuli in the central nervous system (CNS) and is characterized by glial reactivity, induction of cytokines and chemokines and vascular permeability. It may also involve recruitment of peripheral immune cells. A key player in this response is the proinflammatory cytokine interleukin(IL)-1?. IL-1 is rapidly induced in microglia following acute CNS injury or insult, and may be chronically overexpressed in conditions where continuous or repeated harmful stimuli are present, such as in neurodegenerative disorders like Alzheimer's disease (AD). For this reason, IL-1 has long been thought to promote neurodegeneration. Previous work in this lab utilized a novel model of sustained IL-1 production in the brain in conjunction with a mouse model of AD to study the link between IL-1 and AD pathogenesis. This model exhibits a spatially and temporally controlled IL-1 dependent neuroinflammatory response that significantly reduced plaque pathology in the APPswe/PS1 Alzheimer's mouse. Importantly, preliminary work identified increased numbers of microglia surrounding amyloid-? plaques in the IL-1 overexpressing animals. To better characterize the role of endogenous IL-1 in AD pathogenesis, we will quantify endogenous IL-1 expression over a timecourse of plaque development in the APP/PS1 mouse. In order to solidify the link between chronic expression of IL-1 and amyloid clearance, additional studies will employ transgenic and viral vector approaches to achieve sustained upregulation of IL-1 signaling and analyze various AD pathological features. Furthermore, we hypothesize that IL-1 induces microglial-mediated plaque clearance through induction of the innate immune response. This is supported by significant elevation of MCP-1 and increased numbers of microglia surrounding amyloid plaques in our model. To study whether monocytic recruitment from the periphery is responsible for the observed cellular increases, we aim to modify cellular recruitment to the hippocampus during sustained IL-1? expression. Similar methods will be employed to determine whether bone-marrow derived microglia play a role in the observed plaque clearance. Our proposed studies will help to elucidate the role of brain inflammation in neurodegenerative disorders. This is critical since inflammation has been proposed as a therapeutic target in these diseases. Alzheimer's disease is a major public health challenge in our aging society and steps taken to better understand how it develops may lead to new therapies or methods to prevent disease.