Impact of T cells on the CNS during aging and Alzheimer’s disease

衰老和阿尔茨海默病期间 T 细胞对中枢神经系统的影响

• 批准号: 10605221
• 负责人: Casey N Cook
• 金额: $ 48.52万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605221
• 关键词: Adaptive Immune System; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Anti-Inflammatory Agents; Association Learning; Astrocytes; B-Lymphocytes; Behavior; Behavioral; Biological Assay; Blood - brain barrier anatomy; Brain; CCL3 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Central Nervous System; Cognition; Cognitive deficits; Data; Dementia; Deposition; Disease; Disease Progression; Encephalitis; Epidemic; Excision; Gene Expression; Gene Transfer Techniques; Genes; Gliosis; Goals; Granzyme; Hippocampus; Human; Human Amyloid Precursor Protein; Human Genetics; Immune; Immune system; Immunity; Immunofluorescence Immunologic; Inflammation; Inflammatory; Interferon Type II; Kinetics; Knock-in Mouse; Knock-out; Life; Measures; Methodology; Microglia; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; OVA-8; Ovalbumin; Pathologic; Pathology; Peptides; Peripheral; Play; Population; Process; Production; RNA; Risk Factors; Role; Senile Plaques; Sentinel; Shapes; Stimulus; T-Cell Depletion; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TREM2 gene; Tauopathies; Time; Transgenic Animals; Transgenic Organisms; Variant; Western Blotting; Wild Type Mouse; Work; adaptive immune response; adaptive immunity; aged; amyloid formation; amyloid pathology; brain cell; cognitive ability; cognitive function; cognitive performance; conditioned fear; cytokine; experimental study; genetic risk factor; human tissue; in vivo; insight; morris water maze; mouse model; nerve stem cell; neurofibrillary tangle formation; neuroinflammation; normal aging; novel; novel therapeutics; response; stem cell proliferation; tau Proteins; tau-1; transcriptome; transcriptomic profiling; transcriptomics

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disease that results in amyloid β plaque deposition, neurofibrillary tangle (NFT) formation, and life-altering cognitive defects. Many human genetic AD risk factors, including APOE, CLU, and TREM2, modulate neuroinflammation and/or the function of microglia, the central nervous system (CNS) resident innate immune cell. Deletion of all peripheral adaptive immune cells (i.e. CD4+ T cells, CD8+ T cells and B cells) or T cell depletion (i.e. CD4+T cells, CD8+T cells) increased cognitive abilities in amyloidosis and tauopathy models, respectively, and were associated with altered microglial function. Interestingly, aging, another major AD risk factor, is associated with inflammation and we have found that increases in CNS CD8+ T cells found with aging is further exacerbated by amyloidosis. Additionally, enhanced CNS CD8+ T cells numbers are also found during tauopathy. We hypothesize that CD8+ T cells impact cognition and CNS sequelae during tauopathy and age-associated amyloidosis. We predict that CD8+ T cells alter microglia function and transcriptomes as a mechanism for disease modulation. To address this hypothesis, we will utilize aged wild type (WT) control mice, aged APPNL-F/NL-F mice, which express human amyloid precursor protein (APP) or our AAV1 model of tauopathy, respectively, on a normal WT or CD8-/- background, to eliminate CD8+ T cells. We will also conduct similar studies on an OT-I background which contains CD8+ T cells that are not stimulated through their T cell receptor (TCR). We will assess multiple parameters including behavioral/ cognitive performance (using open field assay, elevated plus maze, contextual fear conditioning and morris water maze), immunofluorescence/immunohistology examining plaque deposition, tau phosphorylation, CD8+ T cell localization and microglial/ astrocyte reactivity, flow cytometric analysis of CNS CD8+ T cell function, western blot analysis for total and phosphorylated tau, ex vivo microglial cultures and RT-qPCR to examine cortical and hippocampal gene expression of proinflammatory and anti- inflammatory factors. Furthermore, we will be using single cell transcriptomics to examine the entire RNA transcriptome on a per cell basis to assess CNS CD8+T cell transcriptomes and the impact of CD8+T cells on microglial transcriptomes and subpopulations during normal aging, age-associated amyloidosis or tauopathy. Our proposed work will be the first to define the transcriptomes of CNS CD8+ T cells in the context of age- associated amyloidosis or tauopathy. Additionally, we will address for the first time how CD8+T cells impact behavior/cognition, neuroinflammation, gliosis, microglial transcriptomes and pathology during age-associated amyloidosis or tauopathy. This work will provide highly novel insights into how peripheral and central immunity interact during aging and disease, and could provide the impetus to examine new therapeutic measures for management/alleviation of AD associated CNS sequelae.

项目摘要/摘要 阿尔茨海默病(AD)是一种神经退行性疾病，导致淀粉样蛋白β斑块沉积， 神经原纤维缠结(NFT)的形成和改变生活的认知缺陷。许多人类遗传性阿尔茨海默病风险因素， 包括APOE，CLU和TREM2，调节神经炎症和/或小胶质细胞的功能，中央 神经系统(CNS)居留的先天免疫细胞。删除所有外周适应性免疫细胞(即CD4+ T细胞、CD8+T细胞和B细胞)或T细胞耗尽(即CD4+T细胞、CD8+T细胞)可提高认知能力 分别在淀粉样变性和自发性疾病模型中，并与小胶质细胞功能改变相关。 有趣的是，衰老，另一个主要的AD风险因素，与炎症有关，我们发现 随着年龄的增长，中枢神经系统CD8+T细胞的增加会因淀粉样变性而进一步加重。此外，增强了 在肌萎缩侧索硬化症过程中，CNS CD8+T细胞数量也明显增多。我们假设CD8+T细胞影响 直立性脑病和年龄相关性淀粉样变性中的认知和中枢神经系统后遗症。我们预测CD8+T细胞 改变小胶质细胞的功能和转录本作为疾病调节的机制。要解决这个问题 假设，我们将利用老年野生型(WT)对照组小鼠，老年APPNL-F/NL-F小鼠，表达人类 在正常的WT或CD8-/-上，分别检测淀粉样前体蛋白(APP)或我们的AAV1牛磺酸病变模型 背景：消除CD8+T细胞。我们还将对OT-I背景进行类似的研究， 包含不通过其T细胞受体(TCR)刺激的CD8+T细胞。我们将评估多个 参数包括行为/认知表现(使用开阔场地测试、高架加迷宫、 情景恐惧条件作用和Morris水迷宫)，免疫荧光/免疫组织学检查斑块 沉积，tau磷酸化，CD8+T细胞定位和小胶质细胞/星形胶质细胞反应性，流式细胞仪 CNS CD8+T细胞功能分析、总tau蛋白和磷酸化tau蛋白免疫印迹分析、体外培养小胶质细胞 培养和RT-qPCR检测大脑皮层和海马区促炎症和抗炎基因的表达 炎症因子。此外，我们将使用单细胞转录转录技术来检查整个rna。 转录组在每个细胞的基础上评估CNS CD8+T细胞的转录以及CD8+T细胞对 正常衰老、年龄相关性淀粉样变性或肌萎缩侧索硬化症期间的小胶质细胞转录本和亚群。 我们提出的工作将首次在年龄-T细胞的背景下定义CNS CD8+T细胞的转录。 相关的淀粉样变性或直立性病变。此外，我们将首次讨论CD8+T细胞如何影响 与年龄相关的行为/认知、神经炎症、胶质增生、小胶质细胞转录本和病理学 淀粉样变性或变态反应症。这项工作将为外周免疫和中枢免疫提供非常新颖的见解 在衰老和疾病期间相互作用，并可能提供动力来研究新的治疗措施 AD相关中枢神经系统后遗症的管理/缓解。

项目成果

TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A.

• DOI: 10.1371/journal.pbio.3002028
• 发表时间: 2023-03
• 期刊: PLoS biology
• 影响因子: 9.8

CRISPR interference to evaluate modifiers of C9ORF72-mediated toxicity in FTD.

• DOI: 10.3389/fcell.2023.1251551
• 发表时间: 2023
• 期刊: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• 影响因子: 5.5
• 作者: Pickles, Sarah;Alepuz, Desiree Zanetti;Koike, Yuka;Yue, Mei;Tong, Jimei;Liu, Pinghu;Zhou, Yugui;Jansen-West, Karen;Daughrity, Lillian M. M.;Song, Yuping;DeTure, Michael;Oskarsson, Bjoern;Graff-Radford, Neill R. R.;Boeve, Bradley F. F.;Petersen, Ronald C. C.;Josephs, Keith A. A.;Dickson, Dennis W. W.;Ward, Michael E. E.;Dong, Lijin;Prudencio, Mercedes;Cook, Casey N. N.;Petrucelli, Leonard
• 通讯作者: Petrucelli, Leonard