ASTROCYTE-RELATED MOLECULAR MECHANISMS UNDERLYING ALTERED NEURONAL PLASTICITY IN

项目2：星形胶质细胞相关分子机制在唐氏综合征神经元可塑性改变中的作用本项目旨在了解与唐氏综合征（DS）大脑中星形胶质细胞功能异常相关的分子机制及其在结构和功能可塑性改变中的作用。星形胶质细胞是神经干细胞（NSCs）增殖和分化以及树突棘发育和突触发生的关键调节因子。我们发现DS星形胶质细胞的代谢缺陷与NSCs活力降低和异常脊柱形成直接相关。为了研究星形胶质细胞功能异常的分子通路及其在DS结构和功能神经可塑性改变中的作用，我们提出：1。目的：确定OS星形胶质细胞中与受损的NSCs神经发生和脊柱病理有关的分子改变。我们将定义细胞内AU和线粒体功能障碍在星形胶质细胞分泌缺陷中的作用，以及app和血小板反应蛋白1 （TSP-1）分泌减少在NSCs和脊柱病理中的作用。2. 分析线粒体辅助因子和b分泌酶抑制剂预防或恢复DS星形胶质细胞分泌缺陷及伴随的NSCs和脊柱改变的有效性。3. A)研究DS脑组织星形胶质细胞改变、神经发生与脊柱异常的关系。我们将生成关于星形细胞改变与退行性椎体滑移个体的NSCs和脊柱缺损之间关系的规范性数据。B)评估CSF和血浆中TSP-1水平作为AD生物标志物的有效性。我们建议进行初步研究，以评估血浆和脑脊液中TSP-1水平作为散发性AD和DS+AD患者AD的生物标志物的有效性。我们将利用我们从胎儿脑组织中培养人类神经细胞的丰富经验。神经球形式的NSCs培养，纯星形胶质细胞培养，以及在人星形胶质细胞（正常和DS）上生长的大鼠海马神经元共培养将用于目的1和2。目标3将利用神经病理学中心提供的死后脑样本、脑脊液和血浆样本。统计核心将在所有统计程序中提供反馈。

Project 2: Astrocyte-related molecular mechanisms underlying altered neuronal plasticitv in Down syndrome The goal of this project is to understand the molecular mechanisms associated with abnormal astrocyte function and their role in altered structural and functional plasficity in the Down's syndrome (DS) brain. Astrocytes are critical regulators of neuronal stem cells (NSCs) proliferation and differentiafion as well as dendritic spine development and synaptogenesis. We found metabolic deficits in DS astrocytes directly associated with reduced NSCs viability and aberrant spine formation. To investigate the molecular pathways associated with abnormal astrocyte function and its role in DS altered structural and functional neuroplasticity we propose: 1. To identify the molecular alterations in OS astrocytes responsible for impaired NSCs neurogenesis and spine pathology. We will define the role of intracellular AU and mitochondrial dysfunction in astrocyte secretory deficits, and the role of reduced APPs and thrombospondin 1 (TSP-1) secrefion in NSCs and spine pathology. 2. To analyze the effectiveness of mitochondrial cofactors and B-secretase inhibitors to prevent or revert DS astrocyte secretory deficits and concomitant NSCs and spine alterations. 3. A) To study the relation between astrocyte alterations, neurogenesis and spine anomalies in DS brains. We will generate normative data on the associafion between astrocyte alterations and NSCs and spine deficits in DS individuals. B) To assess the usefulness of TSP-1 levels in CSF and plasma as a biomarker of AD. We propose to perform preliminary studies to evaluate the usefulness of TSP-1 levels in plasma and CSF as a biomarker of AD in sporadic AD and DS+AD pafients. We will take advantage of our extensive experience culturing primary human nerve cells derived from fetal brain tissue. NSCs cultures in the form of neurospheres, pure astrocyte cultures, and cocultures of rat hippocampal neurons growing on top of human astrocytes (normal and DS) will be utilized for aims 1 and 2. Aim 3 will utilize post-mortem brain samples and CSF and plasma samples provided by the Neuropathology Core. The Stafistical Core will provide feedback in all statistical procedures.