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.

项目摘要/摘要 阿尔茨海默氏病（AD）已被视为最优先的神经聚糖疾病之一 研究进步，对患者造成了进步的认知障碍，并负担过多 护理人员和家庭由于缺乏有效的预防或修复治疗 长期以来。 观察到，在 神经变性和炎症，尤其是星形胶质细胞。 功能，电路响应的集成和网络稳态。 这些细胞中细胞内信号传导的动力学在疾病条件下会改变。 由于齿状回的解剖学重要性，因此 海马星形胶质细胞和AD中炎症过程的累及，我们假设：齿状回。 星形胶质细胞在响应不同的神经元电路激活中保持各种信号传导能力能力，并且 信号在差异上容易受到AD病理的影响。 在两个不同的种群中使用选择性电路刺激性标记的钙成像 齿状回的星形胶质细胞，我们将研究星形胶质细胞反应的能力和感染率 神经传递和NUROMODUTION。 专门为星形胶质细胞信号的独特特征设计的专门设计将用于分类和配置文件 肺和分子层星形胶质细胞在对照动物以及AD的5xFAD动物模型中的能力。 此外，我们将尝试确定星形胶质细胞的亚人群和星形胶质细胞多样性的改变 使用单细胞测序，聚类分析和检查差异表达的齿状回 基因和途径。 这些至关重要的细胞中基因表达的改变，因为它们经历了与病理相关的修饰。 该研究的结果将为靶向星形胶质细胞子集的胸膜的潜力而详尽地告知 广告疗法的开发，并将提供成绩单级别的数据库，以测量有效性 潜在干预。