Proteasome contributes to the alpha-secretase pathway of amyloid precursor protein in human cells.
A major histopathological hallmark in Alzheimer's disease consists of the extracellular deposition of the amyloid beta-peptide (A beta) that is proteolytically derived from the beta-amyloid precursor protein (beta APP). An alternative, nonamyloidogenic cleavage, elicited by a protease called alpha-secretase, occurs inside the A beta sequence and gives rise to APP alpha, a major secreted C-terminal-truncated form of beta APP. Here, we demonstrate that human embryonic kidney 293 (HK293) cells contain a chymotryptic-like activity that can be ascribed to the proteasome and that selective inhibitors of this enzyme reduce the phorbol 12,13-dibutyrate-sensitive APP alpha secretion by these cells. Furthermore, we establish that a specific proteasome blocker, lactacystin, also induces increased secretion of A beta peptide in stably transfected HK293 cells overexpressing wild-type beta APP751. Altogether, this study represents the first identification of a proteolytic activity, namely, the proteasome, contributing likely through yet unknown intracellular relays, to the alpha-secretase pathway in human cells.
Marambaud
P
P
IPMC du CNRS, UPR411, Valbonne, France.
Chevallier
N
N
Barelli
H
H
Wilk
S
S
Checler
F
F
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000276:immunology / Q000378:metabolism*; D000918:Antibody Specificity; D016282:Aspartic Acid Endopeptidases; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D009097:Multienzyme Complexes / Q000378:metabolism*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex
D016564:Amyloid beta-Protein Precursor; D002273:Carcinogens; D009097:Multienzyme Complexes; D015240:Phorbol 12,13-Dibutyrate; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D046988:Proteasome Endopeptidase Complex