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Molecular Pathogenesis of Alzheimer's Disease

A novel cleavage of b-amyloid precursor protein (APP), referred to as e-cleavage, occurs downstream of the c-cleavage, and generates predominantly a C-terminal fragment (CTFc) that begins at Val-50, according to amyloid b-protein (Ab) numbering. Whether this cleavage occurs independently of, or is coordinated with, c-cleavage is unknown. Using a cell-free system, we show here that, although Ab40 and CTFc50–99 were the predominant species produced by membranes prepared from cells overexpressing wild-type APP (wtAPP) or wt presenilins (PS) 1 and 2, the production of CTFc49–99, which begins at Leu-49, was remarkably enhanced in membranes from cells overexpressing mutant APP (mtAPP), or mtPS1 and 2 that increase the production of Ab42. Furthermore, a c-secretase inhibitor, which inhibits Ab40 and paradoxically enhances Ab42 production at low concentrations, caused proportion of CTFc50–99 to decrease and that of CTFc49–99 to increase significantly. These results strongly suggest a link between the production of Ab42 and CTFc49–99, and provide an important insight into the mechanisms of altered c-cleavage caused by mtAPP and mtPS1/2.