title: Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein.
abstract: A novel cleavage of beta-amyloid precursor protein (APP), referred to as epsilon-cleavage, occurs downstream of the gamma-cleavage and generates predominantly a C-terminal fragment (CTFgamma) that begins at Val-50, according to amyloid beta-protein (Abeta) numbering. Whether this cleavage occurs independently of, or is coordinated with, gamma-cleavage is unknown. Using a cell-free system, we show here that, although Abeta40 and CTFgamma 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 CTFgamma 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 Abeta42. Furthermore, a gamma-secretase inhibitor, which suppresses Abeta40 production and paradoxically enhances Abeta42 production at low concentrations, caused the proportion of CTFgamma 50-99 to decrease and that of CTFgamma 49-99 to increase significantly. These results strongly suggest a link between the production of Abeta42 and CTFgamma 49-99 and provide an important insight into the mechanisms of altered gamma-cleavage caused by mtAPP and mtPS1/2.
authors.affiliation: Department of Neuropathology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Sato
authors.forename: Naoshi
authors.initials: N
authors.lastname: Dohmae
authors.forename: Yue
authors.initials: Y
authors.lastname: Qi
authors.forename: Nobuto
authors.initials: N
authors.lastname: Kakuda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Misonou
authors.forename: Rie
authors.initials: R
authors.lastname: Mitsumori
authors.forename: Hiroko
authors.initials: H
authors.lastname: Maruyama
authors.forename: Edward H
authors.initials: EH
authors.lastname: Koo
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Koji
authors.initials: K
authors.lastname: Takio
authors.forename: Maho
authors.initials: M
authors.lastname: Morishima-Kawashima
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ihara
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002474:Cell-Free System; D006224:Cricetinae; D005786:Gene Expression Regulation; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments