ASTROCYTE-RELATED MOLECULAR MECHANISMS UNDERLYING ALTERED NEURONAL PLASTICITY IN

项目2：唐氏综合征神经元可塑性改变与星形胶质细胞相关的分子机制本项目的目标是了解唐氏综合征(DS)脑中星形胶质细胞功能异常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、树突棘发育和突触形成的重要调节细胞。我们发现DS星形胶质细胞的代谢缺陷直接与NSCs活性降低和脊柱形成异常有关。为了探讨与星形胶质细胞功能异常相关的分子通路及其在DS结构和功能神经可塑性改变中的作用，我们提出：1.确定OS星形胶质细胞在神经干细胞神经发生和脊髓病理损害中的分子改变。我们将确定细胞内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及其伴发的神经干细胞和脊椎病变的效果。3.1)探讨DS脑内星形胶质细胞改变、神经发生与脊柱畸形的关系。我们将生成关于星形胶质细胞改变与神经干细胞和DS患者脊柱缺陷之间的关联的标准化数据。B)评价脑脊液和血浆中TSP-1水平作为AD生物标志物的价值。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患者的AD生物标志物的有效性。我们将利用我们在培养来自胎儿脑组织的原代人类神经细胞方面的丰富经验。AIM 1和2将使用神经球形式的神经干细胞培养、纯星形胶质细胞培养和生长在人星形胶质细胞上的大鼠海马神经元的共培养(正常和DS)。AIM 3将使用神经病理核心提供的死后脑样本和脑脊液和血浆样本。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.