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

项目摘要 阿尔茨海默病(AD)是一种由遗传和环境因素共同作用的复杂疾病 依赖于炎症作为共同的驱动力。值得注意的是，对中枢神经系统(CNS)的炎性侮辱，如 作为病毒感染，与AD和其他形式的认知能力下降相关，尽管其机制与 阿尔茨海默病的早期神经炎性暴露尚不清楚。病原性感染导致深刻 可以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细胞会渗透到大脑中并持续存在 长期作为组织驻留记忆T(TRM)细胞。虽然TRM细胞在组织中提供了防止再次感染的保护， 它们的存在也可能导致失调的炎症。此外，脑内停留的巨噬细胞，小胶质细胞， 而星形胶质细胞在受到感染后可以在功能和表观遗传上进行重新编程，离开细胞 准备好在再次感染时产生炎症介质。在保护再次感染的同时，它们保持着镇定 大脑TRM细胞和神经胶质细胞的炎症状态可能会使大脑面临潜在的升高和有害的炎症。 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，保护动物免受 暴露在与环境相关的微生物中。因此，本项目旨在开发更具生理性的AD 通过研究连续的病毒感染如何重塑中枢神经系统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脑部炎症，加速神经退行性变和AD的发病。 为此，遗传倾向于出现类AD症状的小鼠将连续感染不同的 病原体在其生命的前半部分复制在一个人的一生中接触到多种病原体。作为 小鼠年龄增长后，将检查它们的组成、转录、表观基因组和免疫功能的变化 细胞、神经胶质细胞和神经元，并寻找AD病理和痴呆的早期迹象。此应用程序将测试是否存在 感染史增加了中枢神经系统中与年龄相关的炎症，如I型和II型干扰素。通过 定义连续感染、慢性炎症和大脑常驻免疫细胞之间的病理联系，这些 研究将解决一个人的感染史和年龄相关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 将揭示大脑TRM细胞的作用以及它们如何调节大脑的炎症基调。考虑 大多数AD病例都是零星的，而且是一种目前缺乏治疗的不可逆转的病理，这是至关重要的 为了更准确地阐明环境因素和免疫系统是如何参与这种疾病的。因此， 这项拨款的目标是开发更具生理学意义的临床前模型，以更好地了解 随着年龄的增长，免疫反应和炎症有助于AD和神经元的健康。

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.