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

淀粉样前体蛋白（APP）被β-和<$-分泌酶加工导致淀粉样β-肽的产生，其是阿尔茨海默病发病机制中的毒性剂。通过分泌酶活性产生Abladium的分子机制仍不清楚。我们的研究支持一个寡聚化依赖性的机制，APP转化为AAP 12。最近，我们发现由三个迄今未被识别的GxxxG基序的甘氨酸残基G29和G33介导的APP跨膜序列（TMS）的二聚化对于最有效的β-分泌酶切割产生A β 42是必需的。我们发现，先前发表的连续的β-分泌酶裂解与底物的二聚体结构（C-末端100个APP残基; β-CTF）密切相关。因此，APP TMS的二聚化是AD的风险因素，提供了特异性降低A β 42的新策略。因此，本研究的目的是表征家族性阿尔茨海默病突变（FAD）影响的<$-分泌酶裂解，这可能是密切相关的影响，我们观察到的GxxxG基序内的AZERO序列。本研究的目的是阐明FAD突变的机制，并在分子水平上表征NSAID对A β 42产生的影响。

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.