SUPRAMOLECULAR ABETA STRUCTURE--GLIAL/NEURONAL RESPONSE

该计划所解决的总体假设是，非- β淀粉样蛋白（Abeta）的纤维状聚集体， 称为A β衍生的活性配体（ADAL）， 引发阿尔茨海默病（AD）特异性细胞反应 导致神经胶质活化，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， 这些活性超分子结构的产生 聚集体可受到其他斑块的影响 组分，特别是衍生自膜神经胶质的那些组分，和 神经胶质细胞的反应促成了一种环境， 促进和增强这些生物活性ADAL的形成。它 本项目的目标是分离和表征ADAL 研究促进其形成的条件，确定 由特定ADAL引起的神经胶质和神经元反应，以及 阐明ADAL-神经胶质-神经元反应的相互作用。更长 长期目标是生物活性Abeta结构和细胞 我们在体外表征的反应，有证据表明，这些 相同的Abeta结构和反应与病理学相关 在AD脑中。为了实现这些目标，三个高度一体化和 提出了互动项目。项目l将准备和 从结构上表征ADAL，检查ADAL的动力学 形成（添加或不添加胶质蛋白，由项目提供 （2）确定影响ADAl-s形成的因素。 ADAL准备将提供给项目2和3进行评估 对神经胶质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， 记录特定分子事件的表现是否诱导 在AD脑中可以检测到神经胶质或神经元培养物中的Abeta。 这些合作和协同作用之间的一组 具有互补专业知识的调查人员提供了一个基础广泛， 但重点突出的方法来解决基本的机械问题 关于AD产生的过程和途径 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， 神经胶质衍生蛋白对淀粉样蛋白毒性的影响， 特定的分子信号通路介导淀粉样蛋白A β- 诱发神经变性这些广泛的可行性数据表明， 成功实现我们提出的目标的可能性很高。 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.