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β-分泌酶处理后产生淀粉样多肽，这是阿尔茨海默病S病发病机制中的有毒物质。分泌酶活性产生A？的分子机制尚不清楚。我们的研究支持APP转化为Aü的依赖于齐聚的机制。最近，我们证明了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)的二聚化是最有效的分泌酶切割产生A？42所必需的。我们发现，以前发表的连续的分泌酶切割与底物的二聚体结构(C-末端100个APP残基；？CTF)密切相关。因此，APP TMS的二聚化是AD的一个风险因素，为AD提供了新的策略，特别是减少了42。因此，本研究的目的是表征影响分泌酶切割的家族性阿尔茨海默病突变(FAD)，该突变可能与我们观察到的A？序列中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Aü42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.