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: 10674878
• 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/10674878
• 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; Brain; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Cells; Cerebrospinal Fluid; Circulation; Clonal Expansion; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Communicable Diseases; Data; Deep Cervical Lymph Node; Deposition; Epitopes; Genes; Genetic Determinism; Genomics; Genotype; Germ Cells; Hematological Disease; Human Herpesvirus 4; Immune; Immune response; Immunity; Immunohistochemistry; Individual; Inflammatory; 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; 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.

项目摘要 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。一个未开发的 APOE在AD病理生物学中的功能是其在免疫调节和病毒感染敏感性中的作用。 最初在周围遇到抗原的T细胞可以通过全身性进入脑脊液（CSF） 循环。但是，此过程的抗原尚不清楚。此处显示的初步数据 展示了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APOE等位基因依赖于CD8 T效应细胞数量的差异 广告血。令人惊讶的是，CD8效应T细胞也存在于患者CSF和T细胞受体（TCR）测序中 表明它们针对爱泼斯坦 - 巴尔病毒（EBV）BZLF1抗原的克隆扩张。此外，分析CSF TCR序列表明在APOE4载体中针对EBV的CD8 T效应细胞克隆膨胀增加。这些 结果表明，抗原经验的T细胞巡逻APOE中受AD影响的大脑的鞘内空间 等位基因特定的方式。我们假设CD8 T细胞巡逻ApoE4 AD患者的血液和CSF， 通过异常的抗病毒抗原控制有助于神经炎症。特定的目标1将利用单细胞RNA 测序（SCRNASEQ）和免疫组织化学确定APOE等位基因对适应性的影响 广告大脑中的免疫力。特定的目标2将使用高吞吐量scrnaseq评估B和T细胞克隆 各种APOE载体的外周血的膨胀与复杂的生物信息学方法相结合 以ApoE等位基因依赖性方式比较抗病毒自适应免疫细胞的转录组。 特定目标3将采用APOE结构校正器和CRISPR基因编辑来确定机械 APOE对抗病毒免疫反应和神经元T细胞杀死的影响。这些研究将进行 在戴维·盖特（David Gate）博士的实验室，他是一名早期研究员，他在研究T细胞的经验丰富的经验，抗病毒 免疫和神经退行性。合作者包括罗伯特·马利（Robert Mahley）博士（格拉德斯通研究所） APOE生物学专业知识，罗伯特·瓦萨（Robert Vassar）（西北大学），他在AD病理学方面具有专业知识， Marsel Mesulam博士，他将通过西北Mesulam提供与患者标本的访问权限 认知神经病学和阿尔茨海默氏病中心。