Dynamic interactions of APP and Presenilin: the GxxxG dimerization motif of the A-beta sequence in amyloid production

APP 和早老素的动态相互作用：淀粉样蛋白产生中 A-β 序列的 GxxxG 二聚化基序

• 批准号: 29795128
• 负责人: Professor Dr. Gerhard Multhaup
• 金额: --
• 依托单位: Department of Pharmacology and Therapeutics
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/29795128?language=en
• 关键词: Dynamic; interactions; APP; Presenilin; GxxxG

Processing of the amyloid precursor protein (APP) by ß- and ¿-secretases leads to the generation of amyloid ß-peptides, which are the toxic agents in the pathogenesis of Alzheimer¿s disease. The molecular mechanisms of the Aß generation by secretase activities have remained unclear. Our studies support an oligomerization-dependent mechanism for the conversion of APP into Aß. Recently we showed that dimerization of the APP transmembrane sequence (TMS) mediated by glycine residues G29 and G33 of three hitherto unrecognised GxxxG motifs is mandatory for most efficient ¿-secretase cleavage to produce Aß42. We found that the previously published consecutive ¿-secretase cleavages are intimately linked to the dimeric structure of the substrate (C-terminal 100 APP residues; ß-CTF). Accordingly, the dimerisation of APP TMS is a risk factor for AD offering new strategies to reduce specifically Aß42. Thus, the aim of this study is to characterize the familial Alzheimer`s disease mutations (FAD) affecting ¿-secretase cleavages that might be intimately linked to the effects that we observed for the GxxxG motif within the Aß sequence. The objectives of this study are to unravel the mechanism of the FAD mutations and to characterize the effects of NSAIDs on Aß42 production at the molecular level.

β -和β -分泌酶对淀粉样蛋白前体蛋白（APP）的加工导致淀粉样蛋白ß-肽的产生，而淀粉样蛋白ß-肽是阿尔茨海默病发病机制中的有毒物质。分泌酶产生asb的分子机制尚不清楚。我们的研究支持寡聚化依赖于APP转化为asb的机制。最近，我们发现由三个迄今未被识别的GxxxG基序的甘氨酸残基G29和G33介导的APP跨膜序列（TMS）的二聚化对于最有效的分泌酶裂解产生Aß42是必需的。我们发现先前发表的连续的¿-分泌酶裂解与底物的二聚体结构（c端100个APP残基；ß-CTF）密切相关。因此，APP TMS的二聚化是AD的一个风险因素，提供了专门降低a ß42的新策略。因此，本研究的目的是表征家族性阿尔茨海默病突变（FAD）影响-分泌酶切割，这可能与我们在asas序列中观察到的GxxxG基序的影响密切相关。本研究的目的是揭示FAD突变的机制，并在分子水平上表征非甾体抗炎药对Aß42产生的影响。