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: 10162474
• 负责人: Elizabeth M Bradshaw
• 金额: $ 67.43万
• 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/10162474
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Autoimmune Diseases; Autopsy; B-Lymphocytes; Bar Codes; Binding; Blood; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Clone Cells; Complex; DNA; Dementia; Dendritic Cells; Doctor of Philosophy; Effector Cell; Etiology; Event; Extracellular Protein; Genes; Genetic Predisposition to Disease; Genetic study; Goals; HLA Antigens; Hippocampus (Brain); Histocompatibility Antigens Class II; Human; Immune; Immune response; Immune system; Impaired cognition; Individual; Infectious Agent; Innate Immune System; Label; Late Onset Alzheimer Disease; Late-Onset Disorder; Libraries; Link; Major Histocompatibility Complex; Microglia; Mind; Morphology; Names; Natural Killer Cells; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenicity; Pathology; Patients; Peptides; Peripheral; Phase; Phenotype; Play; Population; Predisposition; Prefrontal Cortex; Process; Proteins; Public Health; Regulatory T-Lymphocyte; Reporting; Resolution; Risk Factors; Role; Senile Plaques; Specificity; Stains; Susceptibility Gene; System; T cell receptor repertoire sequencing; T-Lymphocyte; Techniques; Technology; Tumor-infiltrating immune cells; Validation; Viral; age related neurodegeneration; antigen binding; antigen-specific T cells; cytokine; cytotoxic; genetic association; genome wide association study; in vivo; insight; macrophage; neuron loss; neuropathology; novel; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; response

PIs: Bradshaw, Elizabeth M., Ph.D. and Wassim Elyaman, Ph.D. Title: Microglia antigen presentation in the CNS of Alzheimer's disease 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.

PI：Bradshaw, Elizabeth M.，博士和 Wassim Elyaman 博士 标题：阿尔茨海默病中枢神经系统中的小胶质细胞抗原呈递 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 衰退和痴呆。全基因组关联研究已经确定了新的 AD 易感位点。 有趣的是，其中几个位点的相关基因与迟发性 AD 的免疫系统有关 (LOAD)，特别是先天免疫系统，包括人类白细胞抗原 (HLA) 区域。这 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 提出。与此同时，病原体假说为可能的致病病因学获得了更多支持 公元。我们建议利用我们对免疫系统的理解与尖端技术相结合 技术以及获得 AD 患者血液和脑部尸检以确定这些神经侵袭性病原体是否 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来：1) 识别肽 由 AD 大脑中高 T 细胞浸润区域和低 T 细胞浸润区域的小胶质细胞 MHC 呈递 细胞浸润； 2) 检查AD中浸润海马的T细胞的抗原反应性和表型， 3) 确定小胶质细胞如何作为病原体的抗原呈递细胞发挥作用，以浸润 T 细胞。