GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42

Processing of the amyloid precursor protein (APP) by beta- and gamma-secretases leads to the generation of amyloid-beta (A beta) peptides with varying lengths. Particularly A beta 42 contributes to cytotoxicity and amyloid accumulation in Alzheimer's disease ( AD). However, the precise molecular mechanism of A beta 42 generation has remained unclear. Here, we show that an amino-acid motif GxxxG within the APP transmembrane sequence (TMS) has regulatory impact on the Ab species produced. In a neuronal cell system, mutations of glycine residues G29 and G33 of the GxxxG motif gradually attenuate the TMS dimerization strength, specifically reduce the formation of A beta 42, leave the level of A beta 40 unaffected, but increase A beta 38 and shorter Ab species. We show that glycine residues G29 and G33 are part of a dimerization site within the TMS, but do not impair oligomerization of the APP ectodomain. We conclude that gamma-secretase cleavages of APP are intimately linked to the dimerization strength of the substrate TMS. The results demonstrate that dimerization of APP TMS is a risk factor for AD due to facilitating A beta 42 production.