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）对损害刺激的局部组织反应，其特征是神经胶质反应，诱导细胞因子和趋化因子和血管渗透性。它也可能涉及募集外周免疫细胞。此反应中的关键参与者是促炎性细胞因子白介素（IL）-1？。急性中枢神经系统损伤或侮辱后，IL-1在小胶质细胞中迅速诱导，并且可能在存在连续或反复的有害刺激的情况下长期过表达，例如在阿尔茨海默氏病（AD）等神经退行性疾病中。因此，长期以来，人们一直认为IL-1会促进神经退行性。该实验室的先前工作利用了与AD小鼠模型结合使用的新型IL-1产生模型，以研究IL-1与AD发病机理之间的联系。该模型在空间和时间控制的IL-1依赖性神经炎症反应上表现出显着降低Appswe/PS1阿尔茨海默氏症小鼠中的斑块病理。重要的是，初步工作确定淀粉样蛋白周围的小胶质细胞数量增加？ IL-1过表达动物中的斑块。为了更好地表征内源性IL-1在AD发病机理中的作用，我们将在APP/PS1小鼠中牙菌斑发育的时期定量内源性IL-1表达。为了巩固IL-1和淀粉样蛋白清除率之间的慢性表达之间的联系，其他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通过诱导先天免疫反应诱导小胶质细胞介导的斑块清除率。这是由MCP-1的显着升高和我们模型中淀粉样斑块周围的小胶质细胞数量增加的支持。为了研究来自外围的单核细胞募集是否负责观察到的细胞增加，我们旨在在持续的IL-1期间修改对海马的细胞募集？表达。将采用类似的方法来确定骨髓衍生的小胶质细胞是否在观察到的斑块清除率中起作用。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。这至关重要，因为已经提出炎症是这些疾病中的治疗靶标。阿尔茨海默氏病是我们老龄化社会中的主要公共卫生挑战，以更好地了解其发展的措施可能会导致预防疾病的新疗法或方法。