Calpain inhibitor I decreases beta A4 secretion from human embryonal kidney cells expressing beta-amyloid precursor protein carrying the APP670/671 double mutation.
We have investigated the effects of the cell-penetrating cysteine protease inhibitors calpain inhibitor I (N-acetyl-Leu-Leu-norleucinal) and calpain inhibitor II (N-acetyl-Leu-Leu-methioninal) on the secretion of the beta-amyloid peptide (beta A4) using transiently transfected cells expressing beta-amyloid precursor protein (APP) with the NL670/671 double mutation. Calpain inhibitor I markedly reduced the amounts of immunoprecipitable beta A4 and p3 peptide released into the culture medium. Within the cells C-terminal APP fragments accumulated. Since beta A4 secretion by cells expressing the 100 amino acid long APP C-terminus was also reduced by calpain inhibitor I, we conclude that this substance directly or indirectly interferes with the gamma-secretase activity responsible for generating the beta A4 and p3 C-termini.
Klafki
H W
HW
Sandoz Pharma Ltd., Basel, Switzerland.
Paganetti
P A
PA
Sommer
B
B
Staufenbiel
M
M
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000196:embryology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; C100690:amyloid beta-protein p3, human; C039304:calpain inhibitors