Immune cell activation and associated blood brain barrier changes across different stages of Alzheimer's disease

项目摘要/摘要 与年龄相关的疾病，如阿尔茨海默病(AD)，正在定义21世纪的公共卫生问题 它是世界上导致残疾的主要原因。越来越多的证据表明，中央 神经系统免疫变化叠加在正在进行的慢性神经变性上可能会有一个主要的 对AD和其他神经退行性疾病的疾病进展的影响。外围设备的作用 在AD的免疫系统中，包括细胞成分在内的先天免疫和获得性免疫仍然存在 神秘莫测。在这项建议中，我们调查了外周和外周血中免疫细胞的特性和丰度 临床前AD、MCI-AD和AD-痴呆患者脑脊液的单细胞分辨 各阶段和正常衰老对照组之间的差异。此外，这项研究的一个新方面将是证实 脑脊液中特定免疫细胞类型与血脑屏障(BBB)改变的严重程度相关 以及不同AD阶段的边缘效应及其对纵向认知功能衰退的影响。我们的总体目标是 在单个细胞分辨率下表征外周和中枢神经系统中免疫细胞的特性和丰度 跨越不同的AD临床阶段并同时进行，以阐明免疫的外周解剖学背景 细胞激活和血脑屏障程度的变化，目的是了解 免疫反应与阿尔茨海默病临床衰退和随后的表型异质性的关系 轨迹。为此，我们将研究脑脊液和外周血中的免疫细胞表型。 强大的单细胞蛋白质组分析技术、质量细胞术和血脑屏障变化将通过 同一受试者的动态增强磁共振成像技术。 将外周和脑脊液适应性和天然免疫细胞激活与血脑屏障变化相结合的数据 跨越AD的不同阶段将有助于制定使用这些标记的明确理由 在淀粉样变性(神经退行性变)框架中。此外，这些见解将有助于未来的治疗 在疾病最有效的临床阶段针对特定的免疫和血脑屏障的变化。结果来自于 这项研究还将使人们能够识别调节免疫细胞内稳态的新机制。 外周和中枢神经系统，以及血脑屏障的状态，为操纵这些免疫细胞提供了潜在的手段 用于未来的治疗目的。

PROJECT SUMMARY/ABSTRACT Age-related diseases, such as Alzheimer's disease (AD), are defining public health concerns of the 21st century and are the leading cause of disability worldwide. A growing body of evidence notes that central nervous system immune changes superimposed on ongoing chronic neurodegeneration may have a major impact on disease progression in AD and other neurodegenerative conditions. The role of the peripheral immune system in AD, including cellular elements of both the innate and adaptive immunity are still enigmatic. In this proposal, we investigate immune cell identity and abundance in the periphery and cerebrospinal fluid (CSF) at single cell resolution among preclinical-AD, MCI-AD, and AD-Dementia stages and among normal aging controls. Furthermore, a novel aspect of this study will be to corroborate the severity of blood brain barrier (BBB) changes associated with specific immune cell profiles noted in CSF and the periphery across AD stages and its impact on longitudinal cognitive decline. Our overall goal is to characterize immune cell identity and abundance in the periphery and the CNS at single cell resolution across different AD clinical stages and in tandem, to clarify the peripheral anatomical context of immune cell activation and the degree of BBB changes, with the goal of understanding the temporal course of immune response in relation to initiation of clinical decline and subsequent phenotypic heterogeneity of AD trajectories. Towards this, we will investigate immune cell phenotypes in the CSF and peripheral blood by a powerful single-cell proteomic analysis technique, mass cytometry, and BBB changes will be delineated by dynamic contrast-enhanced MRI techniques in the same subjects. Data integrating peripheral and CSF adaptive and innate immune cell activation along with BBB changes across different stages of AD will help develop a clear rationale for the use of these markers in the AmyloidTau(Neurodegeneration) framework. Additionally, these insights will help future therapeutic targeting of specific immune and BBB changes at the most effective clinical stage of disease. The results from the study will also enable the identification of novel mechanisms that regulate immune cell homeostasis in the periphery and the CNS, and the state of BBB, providing potential means to manipulate these immune cells for therapeutic purposes in the future.