Myelin-reactivity of a novel population of T cells infiltrating the normal aging monkey brain

浸润正常衰老猴脑的新型 T 细胞群的髓磷脂反应性

基本信息

批准号：
10222549
负责人：
Katelyn Trecartin
金额：
$ 5.1万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-06 至 2023-09-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222549
关键词：
Adaptive Immune System Age Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Antigen Presentation Archives Autoimmune Diseases Autologous Automobile Driving Axon Belief Blood - brain barrier anatomy Blood Circulation Blood Vessels Brain CD3 Antigens CD8B1 gene Cell Culture Techniques Cerebral cortex Cervical lymph node group Chronic Cognitive Cognitive aging Data Demyelinations Development Disease Drug usage Encephalitis Endothelial Cells Exhibits Extravasation FOXP3 gene Flow Cytometry Fresh Tissue Future Gene Expression Gene Expression Profile Goals Human Immune Immunofluorescence Immunologic Immunohistochemistry Impaired cognition Impairment Infiltration Inflammation Inflammatory Integrins Interferon-beta Investigation Investigational Therapies Label Lead Learning Ligands Longevity Macaca mulatta Maintenance Memory Microglia Modeling Monkeys Multiple Sclerosis Myelin Myelin Basic Proteins Myelin Sheath Nerve Degeneration Neurodegenerative Disorders Neurons Pathology Peripheral Phagocyte Bactericidal Dysfunction Phagocytes Phenotype Physicians Play Population Preparation Regulatory T-Lymphocyte Reporting Role Route Scientist Selectins Series Severities Slice Stains T cell therapy T-Lymphocyte Testing Therapeutic Intervention Time Tissue Sample Tissues Training Tumor-infiltrating immune cells Work age related age related neuroinflammation aged aging brain anti-IgG autoreactive T cell autoreactivity behavior test brain parenchyma brain tissue cell injury cognitive testing cytotoxic executive function experimental study functional disability gray matter insight lymphatic drainage neuroinflammation neuron loss normal aging novel novel therapeutics preservation prevent recruit reflectance confocal microscopy sex skills trafficking transcriptome sequencing white matter white matter damage

项目摘要

ABSTRACT Normal human aging is characterized by cognitive impairments in executive function, learning and memory even in the absence of the neurodegeneration of Alzheimer's Disease (AD). While such cognitive aging was long believed to be due to neuronal loss, stereologic investigations of humans free of AD have shown that neurons are not lost, but instead myelin pathology increases and white matter is lost. The rhesus monkey is a valuable model of normal aging as they are spared the overt neurodegeneration of AD but still exhibit cognitive decline similar to humans. Examining the brains of cognitively assessed monkeys, we have found that the myelin shows splitting and ballooning of sheaths that likely impairs axonal conduction velocity and may lead to axon loss and reduced white matter volume. Importantly, myelin pathology correlates with age-related cognitive impairment in the monkey. While the mechanisms underlying this white matter pathology are still unknown, our lab has found that activation and phagocytic dysfunction of microglia increases in the white matter with age and correlates with cognitive decline. In pursuing this problem, I recently discovered that age-related increases in brain inflammation are accompanied by infiltration of peripheral T cells into the white matter in the same loci where myelin pathology is prevalent. These results challenge the concept that the brain is 'immune privileged' and instead might be vulnerable to infiltration of peripheral T cells leading to auto-attack and secondary inflammatory damage. Moreover, T cells do not infiltrate the aging gray matter, suggesting that infiltration is tissue specific and may play a role in age-related white matter pathology. The goal of this project is to determine why T cells infiltrate the aging brain and what their function is within in the white matter in parenchyma. I will perform a series of experiments on brain tissue from cognitively tested rhesus monkeys to test the hypothesis that age-related neuroinflammation leads to parenchymal infiltration of T cells where they are myelin-reactive and contribute to age-related myelin pathology. In Aim 1, I will explore how T cells are trafficked into the brain, what T cell subtypes are present and how T cells are related to myelin pathology. This will be accomplished using immunohistochemistry to label T cells and spectral confocal reflectance (SCoRe) microscopy to quantify myelin. In Aim 2, I will investigate the function of infiltrating T cells by analyzing their gene expression patterns using RNA sequencing and assessing their myelin reactivity and involvement in myelin sheath damage using organotypic slice cultures. To experimentally modulate T cell activity, the cultures will be treated with two therapeutics that target T cells and reduce damage to myelin in multiple sclerosis. In addition to characterizing brain parenchymal T cells with age, I will discover whether infiltrating T cells are myelin reactive and if they contribute to the white matter pathology and the severity of cognitive impairment. These data should identify targets for future experimental and therapeutic interventions to slow or prevent brain aging.

抽象的正常人类衰老的特点是执行功能、学习和记忆等认知障碍，甚至在没有阿尔茨海默病（AD）神经变性的情况下。虽然这种认知老化时间很长人们认为这是由于神经元损失造成的，对没有 AD 的人类进行的体视学研究表明，神经元并没有丢失，而是髓磷脂病理增加并且白质丢失。恒河猴是一种珍贵的正常衰老模型，因为他们没有出现 AD 的明显神经退行性变，但仍然表现出认知能力下降与人类相似。检查认知评估猴子的大脑，我们发现髓磷脂显示鞘的分裂和膨胀可能会损害轴突传导速度并可能导致轴突损失和白质体积减少。重要的是，髓磷脂病理学与年龄相关的认知障碍相关猴子。虽然这种白质病理学的机制仍然未知，但我们的实验室发现白质中小胶质细胞的激活和吞噬功能障碍随着年龄的增长而增加，并与认知能力下降。在研究这个问题时，我最近发现与年龄相关的脑部炎症增加伴随着外周 T 细胞浸润到白质中，其位置与髓磷脂病理学相同很普遍。这些结果挑战了大脑具有“免疫特权”的概念，相反，大脑可能具有“免疫特权”。容易受到外周 T 细胞浸润的影响，导致自身攻击和继发性炎症损伤。此外，T 细胞不会浸润老化的灰质，这表明浸润是组织特异性的，可能是在与年龄相关的白质病理学中发挥作用。该项目的目标是确定 T 细胞浸润的原因衰老的大脑及其在实质白质中的功能。我将表演一系列对经过认知测试的恒河猴的脑组织进行实验，以检验年龄相关的假设神经炎症导致 T 细胞实质浸润，其中髓磷脂反应并有助于与年龄相关的髓磷脂病理学。在目标 1 中，我将探讨 T 细胞如何被贩运到大脑中，T 细胞亚型有哪些 T 细胞的存在以及 T 细胞与髓磷脂病理学的关系。这将通过使用来完成免疫组织化学标记 T 细胞，光谱共焦反射 (SCoRe) 显微镜定量髓鞘质。在目标 2 中，我将通过使用以下方法分析浸润 T 细胞的基因表达模式来研究其功能： RNA 测序并使用评估其髓磷脂反应性和参与髓鞘损伤器官型切片培养物。为了通过实验调节 T 细胞活性，将用两种方法处理培养物针对 T 细胞并减少多发性硬化症中髓磷脂损伤的疗法。除了表征之外脑实质T细胞随着年龄的增长，我会发现浸润性T细胞是否具有髓磷脂反应性，如果它们导致白质病理学和认知障碍的严重程度。这些数据应识别未来减缓或预防大脑衰老的实验和治疗干预的目标。