Altered Diversity of Astrocyte sub-types and Signaling Capabilities in Alzheimer's Disease

阿尔茨海默病中星形胶质细胞亚型和信号传导能力的多样性改变

• 批准号: 10468190
• 负责人: BRENT ASRICAN
• 金额: $ 19.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468190
• 关键词: Acetylcholine; Address; Adult; Age-Months; Aging; Algorithms; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapy; Amyloid beta-Protein; Amyloid deposition; Anatomy; Animal Diseases; Animal Model; Area; Astrocytes; Atrophic; Brain; Calcium; Calcium Signaling; Candidate Disease Gene; Caregivers; Cells; Characteristics; Cholecystokinin; Chronic; Classification; Clinical Trials; Cluster Analysis; Cognitive deficits; Computer Analysis; Control Animal; Data Set; Databases; Development; Disease; Disease Progression; Exhibits; Family; Gene Expression; Genes; Glial Fibrillary Acidic Protein; Glutamates; Hilar; Hippocampus (Brain); Homeostasis; Hypertrophy; Image; Immune; Impaired cognition; Impairment; Inflammation; Inflammatory; Intervention; Learning; Membrane; Memory; Memory Loss; Microdissection; Microglia; Modification; Molecular; Morphology; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurobiology; Neuroglia; Neuropeptides; Neurotransmitters; Pathologic; Pathology; Pathway interactions; Patients; Photons; Physiological; Population; Predisposition; Prevalence; Process; Reporting; Research; Role; Signal Transduction; Site; Testing; Transcript; astrogliosis; base; calcium indicator; dentate gyrus; design; differential expression; effective therapy; effectiveness measure; gamma-Aminobutyric Acid; insight; live cell imaging; memory process; mouse model; neuronal circuitry; neuroregulation; neurotransmission; novel therapeutics; regional difference; response; septohippocampal; single cell sequencing; single-cell RNA sequencing; synaptic function; targeted therapy trials; tau Proteins; theories

Project Summary/Abstract Alzheimer’s Disease (AD) has been identified as one of the highest priority neurobiological diseases in need of research advancement, inflicting progressive cognitive impairment on patients, and excessive burden on caregivers and families. Due to the lack of effective preventative or reparative treatments for AD, it is imperative to identify cellular or circuit factors contributing to the impairments in learning and memory. It has long been observed that glial cells are noticeably altered, morphologically and molecularly, under conditions of neurodegeneration and inflammation, including in AD. Astrocytes in particular have critical roles in synaptic function, integration of circuit responses, and network homeostasis. It is yet unclear how activity-dependent dynamics of intracellular signaling in these cells are altered under disease conditions. Due to the anatomical importance of the dentate gyrus, the heterogeneous signaling characteristics of hippocampal astrocytes, and the involvement of inflammatory processes in AD, we postulate that: dentate gyrus astrocytes maintain diverse signaling capabilities in response to distinct neuronal circuit activation, and that these signals are differentially vulnerable to AD pathology. Using selective circuit stimulation and membrane-tagged calcium imaging in two distinct populations of astrocytes of the dentate gyrus, we will investigate the capabilities and susceptibilities of astrocyte responses to neurotransmission and neuromodulation. Adaptation of calcium datasets to new computational analysis toolsets specifically designed for the unique characteristics of astrocyte signaling will be used to categorize and profile capabilities of hilar and molecular layer astrocytes in control animals and in the 5xFAD animal model of AD. Furthermore, we shall attempt to identify astrocyte sub-populations and alterations in astrocyte diversity within the dentate gyrus, using single-cell sequencing, cluster analysis, and examination of differentially expressed genes and pathways. In this way, we will define the susceptible sub-populations of astrocytes in AD, and reveal alterations in gene expressions in these critically important cells as they undergo pathology-related modifications. Results from this study will greatly inform on the potential of targeting specific subsets of astrocytes in development of AD therapies, and will provide a database of transcript levels by which to measure effectiveness of potential interventions.

项目概要/摘要 阿尔茨海默氏病（AD）已被确定为最需要治疗的神经生物学疾病之一 研究进展，给患者造成进行性认知障碍，并造成过度负担 照顾者和家人。由于AD缺乏有效的预防或修复治疗方法，因此势在必行 识别导致学习和记忆障碍的细胞或电路因素。早已是 观察到，在以下条件下，神经胶质细胞在形态和分子上发生了显着改变 神经退行性变和炎症，包括 AD。星形胶质细胞在突触中尤其具有关键作用 功能、电路响应的整合和网络稳态。目前尚不清楚活动如何依赖 这些细胞内信号传导的动态在疾病条件下发生改变。 由于齿状回的解剖学重要性，其异质信号传导特征 海马星形胶质细胞，以及 AD 中炎症过程的参与，我们假设： 齿状回 星形胶质细胞维持不同的信号传导能力以响应不同的神经元回路激活，并且 这些信号对 AD 病理的影响不同。 在两个不同的群体中使用选择性电路刺激和膜标记钙成像 齿状回星形胶质细胞，我们将研究星形胶质细胞对星形胶质细胞反应的能力和敏感性 神经传递和神经调节。钙数据集适应新的计算分析工具集 专门针对星形胶质细胞信号传导的独特特征而设计，将用于分类和分析 对照动物和 AD 的 5xFAD 动物模型中肺门和分子层星形胶质细胞的功能。 此外，我们将尝试识别星形胶质细胞亚群以及星形胶质细胞多样性的变化 齿状回，使用单细胞测序、聚类分析和差异表达检查 基因和途径。通过这种方式，我们将定义 AD 中星形胶质细胞的易感亚群，并揭示 当这些至关重要的细胞经历病理相关的修饰时，它们的基因表达会发生变化。 这项研究的结果将极大地揭示针对星形胶质细胞特定亚群的潜力 AD 疗法的开发，并将提供转录水平数据库来衡量有效性 潜在的干预措施。