Interdisciplinary Approach to Alzheimer Drug Discovery

描述（由申请人提供）：该计划项目的历史和当前活动证明其重点是通过鉴定对Abeta寡聚化和积累重要的现象的分子基础（例如，蛋白质折叠、蛋白质水平等）。本次竞争性更新的A2修订版中所有项目的主题都集中在细胞表面APP和Abeta代谢的脂蛋白调节上。越来越多的证据表明，低密度和高密度脂蛋白控制APP/Abeta代谢方案的两个分支：载脂蛋白E和J通过各种表面受体调节Abeta清除，而LDL和HDL通过低密度脂蛋白受体样蛋白（LRP）激活信号传导途径，LRP反馈到细胞表面，并通过α-分泌酶激活或抑制APP代谢（“胞外域脱落”）。每个项目提出的主要问题是：（Gandy的项目）他汀类药物通过ROCK激活α-分泌酶。脂蛋白与LRP结合后如何调节这种信号？APP胞外域脱落的磷酸化状态特异性调节剂是什么？（作者：Ghiso）：Abeta的构象转变和寡聚Abeta与载脂蛋白/载脂蛋白受体的相互作用如何影响脑细胞内的蛋白质催化剂，导致Abeta积累和阿尔茨海默病中所见的淀粉样蛋白沉积的伴随形成？（Buxbaum的项目）：主要的ApoE受体在Abeta代谢中起什么作用？（Martins）：能否在体外或体内证明ApoE亚型对Abeta清除的特异性作用？ ApoE蛋白水平在大脑或循环中的作用是什么？ 这些问题将回答使用高度合作的方法和一系列的实验系统，包括纯化的蛋白质，在原代中枢神经系统细胞中的外源基因的表达，和中枢神经系统蛋白质的过量或缺乏水平的遗传诱导。最终，来自这些方法的数据将为有效的抗淀粉样蛋白药物的开发提供信息，这反过来将为阿尔茨海默病中Abeta寡聚化的作用提供最终测试。

DESCRIPTION (provided by applicant): The history and current activity of this Program Project attest to its focus on discovery of druggable anti-Abeta oligomer targets by identifying the molecular bases for the phenomena that appear important for Abeta oligomerization and accumulation (e.g., protein folding, protein levels, etc.). The theme of all Projects in the A2 revision of this competitive renewal focuses on lipoprotein regulation of APP and Abeta metabolism at the cell surface. Growing evidence indicates that low and high density lipoproteins control two limbs of the APP/Abeta metabolic scheme: Apolipoproteins E and J modulate Abeta clearance via a variety of surface receptors, while LDL and HDL activate signalling pathways via the low density lipoprotein receptor-like protein (LRP) that feed back on the cell surface and cause activation or inhibition of APP metabolism by alpha-secretase ("ectodomain shedding"). Major questions posed by each Project are: (Project by Gandy) Statins activate alpha-secretase via ROCK. How do lipoproteins modulate this signal following binding to LRP? What are the phospho-state-specific modulators of APP ectodomain shedding? (Project by Ghiso): How do conformational transitions of Abeta and interactions of oligomeric Abeta with Apolipoproteins/Apolipoprotein receptors affect protein catabolism within brain cells, resulting in Abeta accumulation and the concomitant formation of the amyloid deposits seen in Alzheimer's? (Project by Buxbaum): What role(s) do the major ApoE receptors play in Abeta metabolism? (Project by Martins):. Can ApoE isoform-specific effects on Abeta clearance be demonstrated in vitro or in vivo? What is the role of ApoE protein level in brain or in the circulation? These questions will be answered using a highly collaborative approach and a range of experimental systems, including purified proteins, expression of foreign genes in primary CNS cells, and genetic induction of excessive or deficient levels of CNS proteins. Ultimately, data from such approaches will inform the development of effective anti-amyloid agents, which, in turn, will provide the ultimate test of the role of Abeta oligomerization in Alzheimer's disease.