The carboxyl termini of beta-amyloid peptides 1-40 and 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 (Abeta(1-40)) and Abeta(1-42) by HEK 293 and COS-1 cells expressing beta-amyloid precursor protein with the Swedish double mutation. A multiphasic SDS-polyacrylamide gel electrophoresis system was used for the discrimination of Abeta(1-40) and Abeta(1-42). Calpain inhibitor I, carbobenzoxyl-Leu-Leu-leucinal, and calpeptin were found to reduce the amount of Abeta(1-40) released into the medium in a dose-dependent manner. The reduction of Abeta(1-40) after treatment with 50 microM calpain inhibitor I or 5 microM carbobenzoxyl-Leu-Leu-leucinal was accompanied by a slight increase of Abeta(1-42) released into the medium. These observations suggest that the cleavages at residues 40 and 42 are accomplished by different enzyme activities.
Klafki
H
H
Department of Preclinical Research, Sandoz Pharma Ltd., CH-4002 Basel, Switzerland.
Abramowski
D
D
Swoboda
R
R
Paganetti
P A
PA
Staufenbiel
M
M
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019556:COS Cells; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D007976:Leupeptins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C039304:calpain inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde