The role of apolipoprotein E in Alzheimer's adaptive immunity

载脂蛋白E在阿尔茨海默病适应性免疫中的作用

• 批准号: 10515592
• 负责人: David Gate
• 金额: $ 60.74万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515592
• 关键词: Abeta clearance; Affect; African American; African ancestry; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease risk; Antigens; Apolipoprotein E; Autopsy; B-Cell Antigen Receptor; B-Lymphocytes; BZLF1 gene; Bar Codes; Binding; Bioinformatics; Biology; Blood; Blood Circulation; Brain; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Cells; Cerebrospinal Fluid; Clonal Expansion; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Communicable Diseases; Data; Deep Cervical Lymph Node; Deposition; Epitopes; Genes; Genetic Determinism; Genomics; Genotype; Hematological Disease; Human Herpesvirus 4; Immune; Immune response; Immunity; Immunohistochemistry; Individual; Inflammatory; Institutes; Intrathecal Space; Lasers; Liquid substance; Measures; Meningeal lymphatic system; Microdissection; Nerve Degeneration; Neurology; Neurons; Pathologic; Pathway Analysis; Patients; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Population; Predisposition; Process; Property; Proteomics; RNA; Receptor Cell; Research Personnel; Risk; Role; Source; Specimen; Structure; T cell receptor repertoire sequencing; T-Cell Receptor; T-Lymphocyte; Testing; Transcription Alteration; Universities; Variant; Viral; Viral Antigens; Virus Diseases; adaptive immune response; adaptive immunity; analog; antiviral immunity; apolipoprotein E-3; apolipoprotein E-4; brain cell; cell killing; cytokine; differential expression; disorder risk; effector T cell; experience; immunoregulation; neuroinflammation; neurotoxicity; novel; pathogen; pathogenic virus; peripheral blood; receptor; single-cell RNA sequencing; statistics; theories; transcriptome; transcriptomics

Project Summary Apolipoprotein E (APOE) polymorphic alleles are the main genetic determinants of AD risk. An unexplored function of ApoE in AD pathobiology is that of its role in immune modulation and susceptibility to viral infection. T cells that initially encounter antigen in the periphery can enter the cerebrospinal fluid (CSF) via the systemic circulation. However, the antigens underlying this process are not clear. Preliminary data shown here demonstrates a peripheral adaptive immune signature of AD characterized by an increased number of CD8 effector T cells. Our data further indicates APOE allele-dependent differences in CD8 T effector cell numbers in AD blood. Strikingly, CD8 effector T cells were also present in patient CSF and T cell receptor (TCR) sequencing indicates their clonal expansion against the Epstein-Barr virus (EBV) BZLF1 antigen. Further, analysis of CSF TCR sequences indicates increased CD8 T effector cell clonal expansion against EBV in APOE4 carriers. These results indicate that antigen-experienced T cells patrol the intrathecal space of brains affected by AD in an APOE allele-specific manner. We hypothesize that CD8 T cells patrol the blood and CSF of APOE4 AD patients and contribute to neuroinflammation via aberrant anti-viral antigen control. Specific Aim 1 will utilize single cell RNA sequencing (scRNAseq) and immunohistochemistry to determine the influence of APOE alleles on adaptive immunity in the AD brain. Specific Aim 2 will use high throughput scRNAseq to assess B and T cell clonal expansion in peripheral blood of various APOE carriers combined with sophisticated bioinformatic approaches to compare the transcriptomes of anti-viral adaptive immune cells in an APOE allele-dependent manner. Specific Aim 3 will employ ApoE structure correctors and CRISPR gene editing to determine the mechanistic impact of ApoE on the anti-viral immune response and T cell killing of neurons. These studies will be conducted in the lab of Dr. David Gate, an early-stage investigator who has extensive experience studying T cells, anti-viral immunity and neurodegeneration. Collaborators include Dr. Robert Mahley (Gladstone Institute), who has expertise in ApoE biology, Dr. Robert Vassar (Northwestern University), who has expertise in AD pathobiology, and Dr. Marsel Mesulam, who will provide access to patient specimens through the Northwestern Mesulam Center for Cognitive Neurology and Alzheimer's Disease.

项目概要 载脂蛋白 E (APOE) 多态性等位基因是 AD 风险的主要遗传决定因素。一个未经探索的 ApoE 在 AD 病理学中的功能在于其在免疫调节和对病毒感染的易感性中的作用。 最初在外周遇到抗原的 T 细胞可以通过全身系统进入脑脊液 (CSF) 循环。然而，这一过程背后的抗原尚不清楚。此处显示初步数据 显示 AD 的外周适应性免疫特征，其特征是 CD8 数量增加 效应T细胞。我们的数据进一步表明 CD8 T 效应细胞数量的 APOE 等位基因依赖性差异 AD血。引人注目的是，患者脑脊液和 T 细胞受体 (TCR) 测序中也存在 CD8 效应 T 细胞 表明它们针对 Epstein-Barr 病毒 (EBV) BZLF1 抗原进行克隆扩增。进一步分析CSF TCR 序列表明 APOE4 携带者中针对 EBV 的 CD8 T 效应细胞克隆扩增增加。这些 结果表明，在 APOE 中，经历过抗原的 T 细胞在受 AD 影响的大脑鞘内空间巡逻 等位基因特异性方式。我们假设 CD8 T 细胞在 APOE4 AD 患者的血液和脑脊液中巡逻，并且 通过异常的抗病毒抗原控制导致神经炎症。具体目标 1 将利用单细胞 RNA 测序 (scRNAseq) 和免疫组织化学以确定 APOE 等位基因对适应性的影响 AD 大脑中的免疫力。具体目标 2 将使用高通量 scRNAseq 来评估 B 和 T 细胞克隆 结合复杂的生物信息方法对各种 APOE 携带者的外周血进行扩增 以 APOE 等位基因依赖性方式比较抗病毒适应性免疫细胞的转录组。 Specific Aim 3 将采用 ApoE 结构校正器和 CRISPR 基因编辑来确定其机制 ApoE 对抗病毒免疫反应和 T 细胞杀伤神经元的影响。这些研究将进行 在 David Gate 博士的实验室中，David Gate 博士是一位早期研究人员，在研究 T 细胞、抗病毒药物方面拥有丰富的经验 免疫和神经变性。合作者包括 Robert Mahley 博士（格莱斯顿研究所），他 Robert Vassar 博士（西北大学）拥有 AD 病理学方面的专业知识， Marsel Mesulam 博士，他将通过西北 Mesulam 提供患者标本的获取 认知神经病学和阿尔茨海默病中心。