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

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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.