Infectious history as a determinant of age-related inflammation in Alzheimers disease

感染史是阿尔茨海默病年龄相关炎症的决定因素

基本信息

批准号：
10663042
负责人：
Susan M Kaech
金额：
$ 19万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663042
关键词：
Acceleration Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid Animal Experimentation Animal Model Animals Area Astrocytes Brain CD8B1 gene Cell Communication Cell model Cells Central Nervous System Chronic Cicatrix Complex Data Dementia Development Disease Disease Progression Encephalitis Environment Environmental Risk Factor Epigenetic Process Etiology Exposure to Genetic Genetic Predisposition to Disease Genetic Transcription Goals Grant Health Hippocampus Housing Immune Immune response Immune system Impaired cognition Individual Infection Inflammaging Inflammation Inflammation Mediators Inflammatory Interferon Type II Interferons Knowledge Lead Link Long-Term Effects Macrophage Memory Metabolic Microbe Microglia Mus Myeloid Cells Nerve Degeneration Neurobiology Neurodegenerative Disorders Neuroglia Neurons Pathogenesis Pathogenicity Pathologic Pathology Peripheral Phenotype Physiological Play Pre-Clinical Model Production Reaction Recording of previous events Research Personnel Risk Risk Factors Role Source Sterility Symptoms T cell infiltration T memory cell T-Cell Receptor T-Lymphocyte Testing Time Tissues Viral Virus Diseases Work acute infection adaptive immunity age related age related neurodegeneration aging brain brain health brain tissue cytokine cytotoxic epigenome epigenomics germ free condition high reward high risk immune cell infiltrate immune function immunological status inflammatory marker mouse model neuroinflammation neuron loss novel pathogen protective factors response stem tau Proteins tissue resident memory T cell

项目摘要

Project Summary Alzheimer’s disease (AD) is a complex disease driven by genetic and environmental components, which converge upon inflammation as a common driver. Notably, inflammatory insults to the central nervous system (CNS), such as viral infection, are correlated with AD and other forms of cognitive decline although the mechanisms linking prior neuroinflammatory exposure to later AD development are unclear. Pathogenic infection leads to profound remodeling of tissues that can have long-term effects on the composition of immune cells in tissues including inflammatory and epigenetic states. For example, after infection, memory T cells infiltrate and persist in the brain long-term as tissue-resident memory T (TRM) cells. While TRM cells provide protection against re-infection in tissues, their presence can also lead to dysregulated inflammation. Moreover, the brain resident macrophages, microglia, and astrocytes can be functionally and epigenetically reprogrammed after exposure to infection, leaving the cells poised to produce inflammatory mediators upon re-infection. While protective to re-infection, these poised inflamed states of brain TRM cells and glia may put the brain at risk of potentially elevated and harmful inflammation. Nearly all AD animal research is performed in animals in specific- pathogen free (SPF) conditions, protected from exposure to environmentally-relevant microbes. Therefore, this project aims to develop more physiological AD models by examining how successive viral infections remodel the CNS and brain-resident microglia, astrocytes and TRM cells, to test if this increases brain inflammation and hastens neurodegeneration and AD pathogenesis. To this end, mice genetically predisposed to develop AD-like symptoms will be serially infected with different pathogens over the first half of their lifetime to replicate exposure to multiple pathogens over one’s lifetime. As the mice age, they will be examined for changes in the composition, transcription, epigenome and function of immune cells, glia, and neurons, and look for earlier signs of AD pathology and dementia. This application will test if a history of infection increases age- related inflammation in the CNS, such as Type I and Type II interferons. By defining pathological links between serial infection, chronic inflammation, and brain resident immune cells, these studies will address this gap in knowledge between one’s infection history and age-related inflammation in the brain that supports AD pathogenesis, and define environmental drivers of sporadic AD. Furthermore, these studies will shed light on the role of brain TRM cells and how they regulate the inflammatory tone of the brain. Considering that most cases of AD are sporadic, and it is an irreversible pathology that currently lacks therapies, it is crucial to elucidate more precisely how environmental factors and the immune system are involved in this disease. Thus, the goal of this grant is to develop more physiologically relevant pre-clinical models that can better inform how the immune response and inflammation contribute to AD and neuronal health with age.

项目摘要阿尔茨海默氏病（AD）是一种由遗传和环境成分驱动的复杂疾病，转化在炎症作为常见驱动器时。值得注意的是，对中枢神经系统（CNS）的炎症性侮辱，这样作为病毒感染，尽管机制联系在一起，但与AD和其他形式的认知下降相关事先神经炎症性暴露于后来的AD发育尚不清楚。致病感染导致深刻对组织中可能对组织中免疫细胞组成产生长期影响的组织的重塑炎症和表观遗传状态。例如，感染后，记忆T细胞浸润并持续在大脑中长期作为组织居民记忆t（TRM）细胞。虽然TRM细胞可防止在时机中重新感染，但它们的存在也会导致注射失调。此外，大脑居民巨噬细胞，小胶质细胞，暴露于感染后，可以在功能和表观遗传上进行重新编程，使细胞在功能和表观上进行重编程准备在重新感染后产生炎症介质。在保护重新感染的同时，这些中毒脑TRM细胞和神经胶质的发炎状态可能会使大脑处于潜在升高和有害感染的风险。几乎所有的AD动物研究都是在特定病原体（SPF）条件下进行的动物进行的，受到保护暴露于与环境相关的微生物。因此，该项目旨在开发更多的物理广告通过检查成功的病毒感染如何重塑中枢神经系统和脑居民小胶质细胞，星形胶质细胞和TRM细胞，以测试这是否增加了脑感染并加速神经退行性和AD发病机理。为此，通常倾向于发展出广告样症状的小鼠将被不同的症状感染在他们一生的上半年，病原体在一生中复制多种病原体。作为小鼠年龄，将检查它们的成分，转录，表观基因组和免疫功能的变化细胞，神经胶质和神经元，并寻找早期的AD病理学和痴呆症的迹象。此应用程序将测试是否感染史增加了中枢神经系统中与年龄相关的感染，例如I型和II型干扰素。经过定义连续感染，慢性感染和脑居民免疫核管之间的病理联系，这些研究将解决一个人的感染历史与年龄相关的炎症之间的知识差距支持AD发病机理并定义零星AD的环境驱动因素的大脑。此外，这些研究将阐明脑TRM细胞的作用以及它们如何调节大脑的炎症音调。考虑大多数AD病例都是零星的，它是目前缺乏治疗的不可逆病理学，这是至关重要的更精确地阐明环境因素和免疫系统如何参与该疾病。那，这笔赠款的目的是开发更具身体相关的临床前模型，以更好地告知随着年龄的增长，免疫反应和炎症会导致AD和神经元健康。