The production ratios of AICDe51 and Ab42 by intramembrane proteolysis of bAPP do not always change in parallel

AbstractBackground: During intramembrane proteolysis of b-amyloid protein precursor (bAPP) by presenilin (PS)/g-secretase, e-cleavages at the membrane-cytoplasmic border precede g-cleavages at the middle of the transmembrane domain. Generation ratios of Ab42, a critical molecule for Alzheimer's disease (AD) pathogenesis, and the major Ab40 species might be associated with e48 and e49 cleavages, respectively. Medicines to downregulate Ab42 production have been investigated by many pharmaceutical companies. Therefore, the e-cleavages, rather than the g-cleavage, might be more effective upstream targets for decreasing the relative generation of Ab42. Thus, one might evaluate compounds by analyzing the generation ratio of the bAPP intracellular domain (AICD) species (e-cleavage-derived), instead of that of Ab42.Methods: