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

IL-1 介导的先天免疫激活是阿尔茨海默病斑块清除的基础

• 批准号: 7678367
• 负责人: Sarah Bliss Matousek
• 金额: $ 4.12万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678367
• 关键词: Acetylcholine; Acute; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein Precursor; Animals; Bone Marrow; Brain; Brain region; CCL2 gene; Cells; Chemotactic Factors; Chronic; Deposition; Development; Disease; Encephalitis; Exhibits; Frequencies; Green Fluorescent Proteins; Healed; Hippocampus (Brain); Immune; Immune response; Immunohistochemistry; In Situ; Infiltration; Inflammation; Injury; Interleukin-1; Interleukin-10; Interleukins; Laboratories; Lead; Length; Leukocytes; Link; Mediating; Mediator of activation protein; Messenger RNA; Methods; Microglia; Modeling; Mus; Myeloid Cells; Natural Immunity; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Pathogenesis; Pathology; Peptides; Peripheral; Phagocytosis; Plant Roots; Play; Poison; Production; Proteins; Public Health; Recruitment Activity; Reporting; Role; Sampling; Senile Plaques; Signal Transduction; Societies; Stimulus; Synapses; Synaptophysin; T-Lymphocyte; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Up-Regulation; Vascular Permeabilities; Viral Vector; Work; amyloid peptide; amyloid precursor protein processing; central nervous system injury; chemokine; cytokine; density; esterase; healing; indexing; monocyte; mouse model; neuroinflammation; novel; overexpression; pathogen; prevent; receptor; response; therapeutic target

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.

描述（由申请人提供）：神经炎症是中枢神经系统（CNS）中对有害刺激的局部组织反应，其特征在于神经胶质反应性、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募集。这种反应的关键参与者是促炎细胞因子白细胞介素（IL）-1？。IL-1在急性CNS损伤或损害后在小胶质细胞中被快速诱导，并且在存在连续或重复的有害刺激的情况下，例如在神经退行性疾病如阿尔茨海默病（AD）中，可能长期过表达。由于这个原因，IL-1长期以来一直被认为是促进神经退行性变。本实验室以前的工作利用了一种新的持续IL-1在大脑中产生的模型，结合AD小鼠模型来研究IL-1和AD发病机制之间的联系。该模型表现出空间和时间控制的IL-1依赖性神经炎性反应，其显著降低了APPswe/PS1阿尔茨海默病小鼠中的斑块病理学。重要的是，初步工作确定了淀粉样蛋白周围的小胶质细胞数量增加？在IL-1过表达的动物中的斑块。为了更好地表征内源性IL-1在AD发病机制中的作用，我们将在APP/PS1小鼠斑块发展的时间过程中定量内源性IL-1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，额外的研究将采用转基因和病毒载体方法来实现IL-1信号传导的持续上调并分析各种AD病理特征。此外，我们假设IL-1通过诱导先天性免疫应答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。要研究是否从周边单核细胞招聘是负责观察到的细胞增加，我们的目标是修改细胞招聘海马持续IL-1？表情将采用类似的方法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炎症在神经退行性疾病中的作用。这是至关重要的，因为炎症已被提出作为这些疾病的治疗靶点。阿尔茨海默病是我们老龄化社会的一个主要公共卫生挑战，采取措施更好地了解它的发展可能会导致新的治疗方法或预防疾病的方法。