Microglia antigen presentation in the CNS of Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)是一种以进行性认知为特征的与年龄相关的神经退行性疾病 衰老和痴呆症。全基因组关联研究已经确定了新的AD易感基因。 有趣的是，其中几个基因座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。这个 人类白细胞抗原基因区域与负荷的发现进一步强调了这样一个问题： 小胶质细胞是中枢神经系统(CNS)的抗原提呈细胞，与渗透的T细胞相互作用， 在AD患者的海马体中观察到了哪些抗原，特别是哪些抗原 被呈现出来。同时，病原体假说也为一种可能的致病因素获得了更多支持 阿尔茨海默病的病因。我们建议利用我们对免疫系统的理解结合 尖端技术和获取AD患者的血液和脑尸检来确定这些 神经侵袭性病原体在AD中具有神经毒力。对于这一应用，我们提出了一个多方面的方法 目的：1)鉴定阿尔茨海默病大鼠脑内高T细胞区小胶质细胞MHC呈递的多肽 2)检测T细胞的抗原反应性和表型 3)确定小胶质细胞如何作为AD的抗原提呈细胞发挥作用 病原体渗入T细胞。

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.