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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' 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

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 阿尔茨海默病（AD）是一种由遗传和环境因素驱动的复杂疾病， 作为一种常见的驱动因素。值得注意的是，对中枢神经系统（CNS）的炎性损伤，如 病毒感染，与AD和其他形式的认知能力下降有关，尽管与AD和其他形式的认知能力下降有关的机制是不确定的。 先前的神经炎症暴露与后来的AD发展尚不清楚。病原体感染导致深刻的 可对组织中免疫细胞的组成产生长期影响的组织重塑，包括 炎症和表观遗传状态。例如，感染后，记忆T细胞会浸润并持续存在于大脑中 长期作为组织驻留记忆T（TRM）细胞。虽然TRM细胞提供保护以防止组织中的再感染， 它们的存在也可导致失调的炎症。此外，大脑中的巨噬细胞，小胶质细胞， 星形胶质细胞在感染后可以在功能上和表观遗传学上重新编程， 在再次感染时准备产生炎症介质。虽然保护再次感染，这些准备 大脑TRM细胞和神经胶质的炎症状态可能会使大脑处于潜在的升高和有害炎症的风险中。 几乎所有的AD动物研究都是在无特定病原体（SPF）条件下进行的， 与环境相关的微生物。因此，本项目旨在开发更多的生理AD 通过研究连续的病毒感染如何重塑CNS和脑内驻留的小胶质细胞、星形胶质细胞 和TRM细胞，以测试这是否会增加大脑炎症并加速神经变性和AD发病机制。 为此，遗传上容易出现AD样症状的小鼠将连续感染不同的病毒 病原体在其生命的前半期复制暴露于多种病原体在一个人的一生。为 随着小鼠年龄的增长，它们将被检查免疫球蛋白的组成、转录、表观基因组和功能的变化。 细胞、神经胶质和神经元，并寻找AD病理和痴呆的早期迹象。此应用程序将测试 感染史增加了CNS中与年龄相关的炎症，如I型和II型干扰素。通过 定义了连续感染、慢性炎症和脑内免疫细胞之间的病理联系， 研究将解决一个人的感染史和年龄相关的炎症之间的知识差距， 支持AD发病机制的大脑，并定义散发性AD的环境驱动因素。此外，这些研究 将阐明大脑TRM细胞的作用以及它们如何调节大脑的炎症状态。考虑 大多数AD病例是散发性的，并且是目前缺乏治疗的不可逆病理，因此至关重要的是 更精确地阐明环境因素和免疫系统如何参与这种疾病。因此，在本发明中， 这项资助的目标是开发更多的生理相关的临床前模型，可以更好地告知如何 免疫应答和炎症有助于AD和神经元健康。