ASTROCYTE-RELATED MOLECULAR MECHANISMS UNDERLYING ALTERED NEURONAL PLASTICITY IN

项目二：唐氏综合征神经元可塑性改变的星形胶质细胞相关分子机制本项目的目的是了解与异常星形胶质细胞功能相关的分子机制及其在唐氏综合征（DS）大脑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（neuronal stem cells，NSCs）增殖分化、树突棘发育和突触形成的重要调节因子。我们发现DS星形胶质细胞的代谢缺陷与NSCs活力降低和异常棘形成直接相关。为了研究与星形胶质细胞功能异常相关的分子通路及其在DS改变的结构和功能神经可塑性中的作用，我们提出：1。确定OS星形胶质细胞中负责受损的NSCs神经发生和脊柱病理学的分子改变。我们将明确细胞内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APPs和血小板反应蛋白1（TSP-1）分泌减少在神经干细胞和脊柱病理中的作用。2.分析线粒体辅因子和B-分泌酶抑制剂预防或逆转DS星形胶质细胞分泌缺陷以及伴随的NSC和脊柱改变的有效性。3. A）研究DS脑中星形胶质细胞改变、神经发生和脊柱异常之间的关系。我们将生成关于DS个体中星形胶质细胞改变和NSC和脊柱缺陷之间的关联的规范性数据。B）评估CSF和血浆中TSP-1水平作为AD生物标志物的有用性。我们建议进行初步研究，以评估血浆和CSF中TSP-1水平作为散发性AD和DS+AD患者的AD生物标志物的有用性。我们将利用我们丰富的经验，培养来自胎儿脑组织的原代人类神经细胞。神经球形式的NSC培养物、纯星形胶质细胞培养物和在人星形胶质细胞（正常和DS）上生长的大鼠海马神经元的共培养物将用于目标1和2。目标3将利用神经病理学核心提供的死后脑样本和CSF及血浆样本。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.