Microglia antigen presentation in the CNS of Alzheimer's disease

阿尔茨海默病中枢神经系统中小胶质细胞抗原呈递

• 批准号: 10827697
• 负责人: Elizabeth M Bradshaw
• 金额: $ 41.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10827697
• 关键词: Administrative Supplement; Affect; Aging; Algorithms; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Autoimmune Diseases; Autopsy; Behavior; Biological Assay; Blood; Brain; Brain region; Cell Aging; Cells; Central Nervous System; Cerebrospinal Fluid; Chronic; Clonal Expansion; Clonality; Cognition; Communicable Diseases; Computational algorithm; Cytotoxic T-Lymphocytes; Dementia; Development; Etiology; FDA approved; Functional disorder; Galactose Binding Lectin; Genes; Goals; HLA Antigens; Hippocampus; Homeostasis; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunologic Monitoring; Immunologic Surveillance; Impaired cognition; Individual; Infection; Innate Immune System; Late Onset Alzheimer Disease; Leptomeninges; Ligands; Link; Maps; Measurement; Meningeal; Meningeal lymphatic system; Meninges; Microglia; Nerve Degeneration; Neurons; New York; Organism; PTPRC gene; Pathogenicity; Patient-Focused Outcomes; Peptides; Peripheral; Persons; Phenotype; Play; Population; Population Heterogeneity; Predisposition; Process; Protocols documentation; Public Health; RNA; Risk Factors; Role; Severities; Signal Pathway; Sorting; Specificity; Susceptibility Gene; System; T cell clonality; T cell infiltration; T cell receptor repertoire sequencing; T cell therapy; T-Lymphocyte; Technology; Time; Tissues; Work; age related neurodegeneration; aged; computerized tools; cytokine; cytotoxic; cytotoxic CD8 T cells; exhaust; exhaustion; experimental study; fighting; genome wide association study; glymphatic system; human old age (65+); human tissue; immunosenescence; improved; microbial; nervous system disorder; neuroregulation; neurotransmission; neurotropic virus; novel; pathogen; receptor; senescence

Project Summary/Abstract Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. Genome-wide association studies have identified novel AD susceptibility loci. Interestingly the associated genes at several of these loci implicate the immune system in late-onset AD (LOAD), specifically the innate immune system, including the human leukocyte antigen (HLA) region. The finding of the HLA region being genetically associated with LOAD further emphasizes the question of how microglia, the antigen-presenting cells of the central nervous system (CNS), interact with infiltrating T cells, which have been observed in the hippocampus of AD patients, and specifically what antigens are being presented. In parallel, the pathogen hypothesis has garnered more support for a possible pathogenic etiology of AD. We propose to leverage our understanding of the immune system combined with cutting-edge technology and access to AD patient blood and brain autopsies to determine if these neuroinvasive pathogens are neurovirulent in AD. For this application, we propose a multifaceted approach to: 1) identify the peptides being presented by the MHC of microglia in the AD brain in regions of high T cell infiltration and areas of low T cell infiltration; 2) examine the antigen reactivity and phenotype of T cells infiltrating the hippocampus in AD, and 3) determine how microglia function as antigen-presenting cells of pathogens to infiltrating T cells.

项目概要/摘要 阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是进行性认知障碍 全基因组关联研究发现了新的 AD 易感位点。 其中几个位点的相关基因暗示晚发性 AD 中的免疫系统 (LOAD)，特别是先天免疫系统，包括人类白细胞抗原 (HLA) 区域。 HLA 区域与 LOAD 具有遗传相关性的发现进一步强调了以下问题： 小胶质细胞是中枢神经系统 (CNS) 的抗原呈递细胞，与浸润性 T 细胞相互作用， 在 AD 患者的海马体中观察到了哪些抗原，具体是什么抗原 与此同时，病原体假说也为可能的病原体获得了更多支持。 我们建议将我们对免疫系统的理解与 AD 的病因学相结合。 尖端技术和获得 AD 患者血液和脑部尸检以确定这些 神经侵袭性病原体在 AD 中具有神经毒性。对于此应用，我们提出了一种多方面的方法。 1) 鉴定 AD 脑中高 T 细胞区域小胶质细胞 MHC 呈递的肽 浸润和低T细胞浸润区域；2)检查T细胞的抗原反应性和表型 浸润 AD 中的海马体，3) 确定小胶质细胞如何作为抗原呈递细胞发挥作用 病原体侵入T细胞。