Potential Link between Amyloid β-Protein 42 and C-terminal Fragment γ 49-99 of β-Amyloid Precursor Protein

Abstract

A novel cleavage of β-amyloid precursor protein (APP), referred to as ε-cleavage, occurs downstream of the γ-cleavage and generates predominantly a C-terminal fragment (CTFγ) that begins at Val-50, according to amyloid β-protein (Aβ) numbering. Whether this cleavage occurs independently of, or is coordinated with, γ-cleavage is unknown. Using a cell-free system, we show here that, although Aβ40 and CTFγ 50-99 were the predominant species produced by membranes prepared from cells overexpressing wild-type (wt) APP and wt presenilin (PS) 1 or 2, the production of CTFγ 49-99, which begins at Leu-49, was remarkably enhanced in membranes from cells overexpressing mutant (mt) APP or mtPS1/2 that increases the production of Aβ42. Furthermore, a γ-secretase inhibitor, which suppresses Aβ40 production and paradoxically enhances Aβ42 pro. duction at low concentrations, caused the proportion of CTFγ 50-99 to decrease and that of CTFγ 49-99 to increase significantly. These results strongly suggest a link between the production of Aβ42 and CTFγ 49-99 and provide an important insight into the mechanisms of altered γ-cleavage caused by mtAPP and mtPS1/2.