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

阿尔茨海默病不同阶段的免疫细胞激活和相关血脑屏障变化

• 批准号: 10688122
• 负责人: JAGAN AYYAPPAN PILLAI
• 金额: $ 75.33万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688122
• 关键词: Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid beta-Protein; Anatomy; Animals; Benchmarking; Biological Markers; Blood - brain barrier anatomy; CCL2 gene; Cell Separation; Cells; Central Nervous System; Cerebrospinal Fluid; Chronic; Clinical; Cognition; Cognitive; Cytometry; Dementia; Development; Disease; Disease Progression; Elements; Functional disorder; Future; Goals; Hemorrhage; Heterogeneity; Homeostasis; Human; Image; Immune; Immune System Diseases; Immune Targeting; Immune response; Immune system; Immunophenotyping; Impaired cognition; Individual; Inflammation; Intervention; Knowledge; MMP3 gene; Magnetic Resonance Imaging; Measurement; Measures; Methods; Natural Immunity; Nature; Nerve Degeneration; Participant; Pathologic; Peripheral; Peripheral Nervous System; Phenotype; Phosphorylation; Population; Predisposition; Production; Proteomics; Public Health; Research; Resolution; Role; Severities; Signaling Protein; System; TNFRSF1B gene; TREM2 gene; Techniques; Therapeutic; Time; abeta deposition; adaptive immune response; adaptive immunity; age related; blood-brain barrier permeabilization; chemokine; cognitive change; cohort; contrast enhanced; cytokine; data integration; disability; flexibility; genetic variant; high dimensionality; human subject; immune activation; inflammatory marker; insight; mild cognitive impairment; neuroprotection; normal aging; novel; novel marker; peripheral blood; pre-clinical; targeted treatment; tau Proteins; therapeutic target; treatment response

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.

项目总结/摘要 阿尔茨海默病（AD）等与糖尿病相关的疾病正在定义21世纪的公共卫生问题 这是世纪的主要问题，也是全世界残疾的主要原因。越来越多的证据表明， 神经系统免疫变化叠加在正在进行的慢性神经退行性变上， 对AD和其他神经退行性疾病进展的影响。外围设备的作用 AD中的免疫系统，包括先天性和适应性免疫的细胞成分，仍然是 神秘莫测在这个提议中，我们研究了外周中的免疫细胞特性和丰度， 临床前AD、MCI-AD和AD-痴呆患者单细胞分辨率下的脑脊液（CSF） 阶段和正常老化对照之间。此外，这项研究的一个新方面将是证实， 与CSF中观察到的特异性免疫细胞谱相关的血脑屏障（BBB）变化的严重程度 和周边跨越AD阶段及其对纵向认知下降的影响。我们的总体目标是 以单细胞分辨率表征外周和CNS中的免疫细胞特性和丰度 在不同的AD临床阶段和串联，以澄清免疫的外周解剖背景， 细胞活化和BBB变化的程度，目的是了解 免疫应答与AD临床衰退起始和随后的表型异质性相关 轨迹为此，我们将研究免疫细胞表型在CSF和外周血中， 强大的单细胞蛋白质组学分析技术、质谱细胞计数和血脑屏障变化将通过以下方式描述： 动态对比增强MRI技术。 数据整合外周和CSF适应性和先天免疫细胞活化沿着BBB变化 跨越AD的不同阶段将有助于为使用这些标记物制定明确的理由 在淀粉样Tau（神经变性）框架中。此外，这些见解将有助于未来的治疗 在疾病的最有效临床阶段靶向特异性免疫和BBB变化。的结果 这项研究还将能够鉴定调节免疫细胞稳态的新机制， 外周和CNS，以及BBB的状态，提供了操纵这些免疫细胞的潜在手段 用于将来的治疗目的。