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: 10301864
• 负责人: BRENT ASRICAN
• 金额: $ 23.33万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301864
• 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; Structure of molecular layer of cerebellar cortex; 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.

项目总结/摘要 阿尔茨海默病（AD）已被确定为需要治疗的最优先神经生物学疾病之一。 研究进展，对患者造成进行性认知障碍，以及对患者造成过度负担。 照顾者和家庭。由于缺乏有效的预防或修复性治疗AD， 以确定导致学习和记忆障碍的细胞或电路因素。人们早就 观察到神经胶质细胞在形态和分子上都发生了明显的变化， 神经变性和炎症，包括AD。特别是星形胶质细胞在突触 功能，电路响应的整合和网络稳态。目前尚不清楚活动依赖性 这些细胞中的细胞内信号传导动力学在疾病条件下改变。 由于齿状回在解剖学上的重要性， 海马星形胶质细胞，并参与炎症过程中AD，我们推测：齿状回 星形胶质细胞响应于不同的神经元回路激活而保持不同的信号传导能力，并且 这些信号对AD病理学的脆弱性不同。 在两个不同的人群中使用选择性电路刺激和膜标记钙成像， 齿状回的星形胶质细胞，我们将研究星形胶质细胞对 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， 对照动物和AD的5xFAD动物模型中的门和分子层星形胶质细胞的能力。 此外，我们将尝试识别星形胶质细胞亚群和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，并检查差异表达 基因和途径。通过这种方式，我们将确定AD中星形胶质细胞的易感亚群，并揭示 这些至关重要的细胞在经历病理学相关修饰时基因表达的改变。 这项研究的结果将极大地揭示靶向星形胶质细胞特定亚群的潜力， 开发AD疗法，并将提供一个转录水平数据库，以衡量有效性 潜在的干预。