THE CARBOXYL TERMINI OF BETA-AMYLOID PEPTIDE-1-40 AND PEPTIDE-1-42 ARE GENERATED BY DISTINCT GAMMA-SECRETASE ACTIVITIES

We have studied the effects of peptide aldehyde protease inhibitors on the secretion of beta-amyloid peptide 1-40 (A beta(1-40)) and A beta( 1-42) by HEK 293 and COS-1 cells expressing beta-amyloid precursor pro tein with the Swedish double mutation. A multiphasic SDS-polyacrylamid e gel electrophoresis system was used for the discrimination of A beta (1-40) and A beta(1-42). Calpain inhibitor I, carbobenzoxyl-Leu-Leu-le ucinal, and calpeptin were found to reduce the amount of A beta(1-40) released into the medium in a dose-dependent manner. The reduction of A beta(1-40) after treatment with 50 mu M calpain inhibitor I or 5 mu M carbobenzoxyl-Leu-Leu-leucinal was accompanied by a slight increase of A beta(1-42) released into the medium. These observations suggest t hat the cleavages at residues 40 and 42 are accomplished by different enzyme activities.