SUPRAMOLECULAR ABETA STRUCTURE--GLIAL/NEURONAL RESPONSE

这一计划解决的总体假设是，非 纤维聚集的淀粉样β蛋白(Abeta)，我们 称为Abeta衍生的活性配体(ADAL)在 触发阿尔茨海默病(AD)特异性细胞反应 导致神经胶质细胞激活，神经元可塑性障碍， 退化并最终导致细胞死亡。我们进一步建议， Abeta活性超分子结构的生成 聚集体可受其他斑块的存在的影响 成分，特别是那些来自胶质膜的成分，以及 神经胶质细胞的反应对环境的贡献 促进和增强这些生物活性Adals的形成。它 是这个项目的目标是分离和描述Adals 研究促进它们形成的条件，确定 特定腺苷引起的神经胶质和神经元反应，以及 阐明腺体-神经胶质-神经元反应的相互作用。一个更长的 学期目标是生物活性Abeta结构与细胞的相关性 我们在体外描述的反应，有证据表明这些 相同的Abeta结构和反应与病理有关 在AD大脑中。为了实现这些目标，三个高度整合和 提出了互动项目。L项目将筹备和 从结构上表征腺苷，考察腺苷的动力学 形成(添加或不添加由Project提供的胶质蛋白 2)，并确定哪些因素影响阿德尔-S的形成。 将向项目2和项目3提供ADAL准备工作以供评估 分别对神经胶质细胞和神经元的生物活性。 还将对AD脑组织进行免疫组织化学研究，以 记录特定分子事件的表现是否导致 阿尔茨海默病患者脑组织中可检测到神经胶质细胞或神经元中的Abeta。 这些合作和协同的互动在一组 具有互补专业知识的调查人员提供了一个基础广泛的 但重点解决基本机械问题的方法 关于AD发生的过程和途径 神经病理学。此外，我们的合作还导致了 关于神经毒性淀粉样蛋白起源的重大新发现， 胶质衍生蛋白对淀粉样蛋白毒性的影响，以及 介导淀粉样蛋白Aβ的特定分子信号通路 诱发神经退行性变。这些广泛的可行性数据表明 成功完成我们提出的建议的可能性很大 目标。

The overall hypothesis addressed by this program is that non- fibrillar aggregated assemblies of amyloid beta (Abeta) which we refer to as Abeta-derived active ligands (ADALs) are active in triggering Alzheimer's disease (AD)-specific cellular responses leading to glial activation, neuronal plasticity malfunction, degeneration and ultimately cell death. We further propose that the generation of these active supramolecular structures of Abeta aggregates can be influenced by the presence of other plaque components, particularly those components derived film glia, and that responses of glial cells contribute to an environment that facilitates and enhances the formation of these bioactive ADALs. It is the goal of this program to isolate and characterize the ADALs examine the conditions that promote their formation, determine the glial and neuronal responses elicited by specific ADALs, and elucidate the interplay of ADAL-glial-neuronal responses. A longer term goal is correlation of bioactive Abeta structures and cellular responses that we characterize in vitro with evidence that these same Abeta structures and responses are associated with pathology in AD brain. Towards these goals, three highly integrated and interactive projects are proposed. Project l will prepare and characterize ADALs structurally, examine the kinetics of ADAL formation (with or without added glial proteins provided by project 2), and determine what factors influence the formation of ADAl-s. The ADAL preps will be provided to Projects 2 and 3 for evaluation of bioactivity on glia and neurons, respectively. Immunohistochemical studies on AD brain tissue will also be done to document whether manifestations of specific molecular events induced by Abeta in glia or neuronal cultures can be detected in AD brain. These cooperative and synergistic interactions among a group of investigators with complementary expertises provide a broad-based, yet focused approach to addressing fundamental mechanistic questions about the processes and pathways involved in generation of AD neuropathology. In addition, our collaborations have led to significant new discoveries about the genesis of neurotoxic amyloid, the influence of glial-derived proteins on amyloid toxicity, and the specific molecular signaling pathways that mediate amyloid Abeta- induced neurodegeneration. These extensive feasibility data suggest a high probability for successful accomplishment of our proposed goals.