Toll-like Receptors and Innate Immune Activation in Alzheimer's Disease

阿尔茨海默病中的 Toll 样受体和先天免疫激活

• 批准号: 8197969
• 负责人: Brent David Cameron
• 金额: $ 2.76万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197969
• 关键词: Adaptor Signaling Protein; Address; Adopted; Affect; Age; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; Biochemical; Biology; Brain; CD14 gene; CD36 gene; CD47 Antigen; CD47 gene; Cell Surface Receptors; Cell surface; Cessation of life; Characteristics; Chronic; Cognition; Complex; Conflict (Psychology); Dementia; Deposition; Disease; Disease Marker; Disease Progression; Elements; Equilibrium; Family; Future; Generations; Goals; Healthcare Systems; Homeostasis; IRAK4 gene; Immune response; Immune system; Integrins; Interleukin-4; Knock-in Mouse; Knock-out; Lead; Left; MAPK14 gene; Measurement; Mediating; Membrane; Methods; Microglia; Modeling; Monitor; Mus; Neuraxis; Neurodegenerative Disorders; Pathogenesis; Pathology; Pb clearance; Persons; Phagocytosis; Phenotype; Phosphotransferases; Physiological; Play; Process; Production; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proteins; Reactive Oxygen Species; Receptor Signaling; Role; SR-B proteins; Senile Plaques; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Surveys; TLR2 gene; TLR4 gene; Testing; Therapeutic Intervention; Time; Tissues; Toll-like receptors; Work; age related; amyloid pathology; amyloid precursor protein processing; brain tissue; cytokine; effective therapy; extracellular; hyperphosphorylated tau; immune activation; in vivo; interleukin-1 receptor-associated kinase; macrophage; member; mouse model; neuron loss; pathogen; public health relevance; receptor; response; scavenger receptor; secretase; stoichiometry

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of age-related dementia, affecting millions of persons worldwide and presenting a significant burden to healthcare systems. Pathological hallmarks of the disease are the deposition of beta amyloid (fA2) protein as insoluble, extracellular fibrillar amyloid plaques in the brain parenchyma and intraneuronal accumulation of hyperphosphorylated tau. Microglia, the brain's tissue resident macrophage, mount a proinflammatory immune response against A2 plaques. Microglia recognize A2 plaques through the toll-like receptors (TLRs). TLRs orchestrate the proinflammatory state through the interleukin-1 receptor-associated kinases (IRAKs). However, microglia can exist in different states of activation that have different physiological consequences. Furthermore, transition between these states can also influence their pro or anti-inflammatory characteristics. Loss of the kinase activity of the signaling molecule IRAK4 blocks the ability of macrophages to adopt a classical activation state. The hypothesis driving this work is that the activation state of microglia in Alzheimer's disease has a direct impact on disease pathogenesis and that a switch between activation state occurs during disease progression. One specific goal of this proposal is to test if loss of IRAK4 kinase activity decreases amyloid pathology in a mouse model of Alzheimer's disease. This will be achieved by crossing IRAK4 kinase-dead mice with a mouse model of AD. Animals will be assessed at various time points during disease for markers of microglial activation such as TNF1 and Arginase1. AD pathology will be evaluated through analysis of A2 levels and plaque burden. A second specific goal of this proposal is to determine if loss of IRAK4 kinase activity alters the activation status of microglia and their response to amyloid fibrils. Microglia from WT and IRAK4 KD mice will be primed to an alternative activation status with IL-4 and then presented with fA2. Their activation status will be monitored through cytokine measurements and NF:B activation status. Further, activation of signaling pathways such as p38 and Jnk, which are involved in classical activation and upregulated in AD, will be assessed through biochemical methods. By characterizing the role that activation status of microglia plays in AD pathogenesis, more effective future therapeutic interventions will be able to be developed. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a chronic neurodegenerative disease that affects millions of persons. This project addresses the role that the immune system plays in Alzheimer's disease. A better understanding of the immune response in Alzheimer's disease will lead to more effective treatments.

描述（由申请人提供）：阿尔茨海默病 (AD) 是最常见的与年龄相关的痴呆症，影响着全世界数百万人，给医疗保健系统带来了巨大的负担。该疾病的病理特征是 β 淀粉样蛋白 (fA2) 在脑实质中沉积为不溶性细胞外纤维状淀粉样斑块，以及过度磷酸化 tau 蛋白在神经元内积聚。小胶质细胞是大脑组织中的巨噬细胞，可针对 A2 斑块发起促炎性免疫反应。小胶质细胞通过 Toll 样受体 (TLR) 识别 A2 斑块。 TLR 通过白细胞介素 1 受体相关激酶 (IRAK) 协调促炎状态。然而，小胶质细胞可以以不同的激活状态存在，从而产生不同的生理后果。此外，这些状态之间的转变也会影响它们的促炎或抗炎特性。信号分子 IRAK4 激酶活性的丧失会阻碍巨噬细胞采取经典激活状态的能力。推动这项工作的假设是，阿尔茨海默病中小胶质细胞的激活状态对疾病发病机制有直接影响，并且在疾病进展过程中会发生激活状态之间的切换。该提案的一个具体目标是测试 IRAK4 激酶活性的丧失是否会减少阿尔茨海默病小鼠模型中的淀粉样蛋白病理。这将通过将 IRAK4 激酶死亡小鼠与 AD 小鼠模型杂交来实现。将在疾病期间的不同时间点对动物进行小胶质细胞活化标记物（例如 TNF1 和精氨酸酶 1）的评估。 AD 病理学将通过分析 A2 水平和斑块负荷进行评估。该提案的第二个具体目标是确定 IRAK4 激酶活性的丧失是否会改变小胶质细胞的激活状态及其对淀粉样原纤维的反应。来自 WT 和 IRAK4 KD 小鼠的小胶质细胞将通过 IL-4 进入替代激活状态，然后呈现 fA2。它们的激活状态将通过细胞因子测量和 NF:B 激活状态进行监测。此外，将通过生化方法评估 p38 和 Jnk 等信号通路的激活，这些信号通路参与 AD 的经典激活和上调。通过表征小胶质细胞的激活状态在 AD 发病机制中所起的作用，未来将能够开发出更有效的治疗干预措施。 公共卫生相关性：阿尔茨海默病是一种影响数百万人的慢性神经退行性疾病。该项目探讨了免疫系统在阿尔茨海默病中的作用。更好地了解阿尔茨海默病的免疫反应将带来更有效的治疗方法。