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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：
9911338
负责人：
Katelyn Trecartin
金额：
$ 5万
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/9911338
关键词：
Adaptive Immune System Age Age-associated memory impairment Aging Alzheimer&apos s Disease 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-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 therapeutic target 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.

摘要