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

项目摘要/摘要 阿尔茨海默病(AD)已被确定为需要高度重视的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，以及过度负担 照顾者和家人。由于缺乏对阿尔茨海默病的有效预防性或修复性治疗，因此势在必行 以确定导致学习和记忆障碍的细胞或电路因素。一直以来都是 观察到神经胶质细胞在形态和分子上都发生了显著的变化 神经变性和炎症，包括阿尔茨海默病。尤其是星形胶质细胞在突触中起着关键作用 功能、电路响应的集成和网络动态平衡。目前还不清楚对活动的依赖程度 在疾病条件下，这些细胞内信号的动态变化。 由于齿状回在解剖学上的重要性，海马齿状回信号的异质性 海马区星形胶质细胞和炎症过程在AD中的参与，我们假设：齿状回 星形胶质细胞维持不同的信号能力，以响应不同的神经元电路激活，并且 这些信号不同地易受AD病理的影响。 在两个不同的人群中使用选择性回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的独特特征设计的信号将被用来分类和描述 对照动物和阿尔茨海默病5xFAD动物模型中肺门和分子层星形胶质细胞的能力。 此外，我们将尝试确定星形胶质细胞亚群和星形胶质细胞多样性的变化。 利用单细胞测序、聚类分析和差异表达检测 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与病理相关的修饰时基因表达的变化。 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可能性。 开发AD疗法，并将提供一个衡量疗效的成绩单水平数据库 潜在的干预措施。

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.