Lactacystin decreases amyloid-beta peptide production by inhibiting beta-secretase activity.
The human amyloid precursor protein (APP) is processed by the nonamyloidogenic and the amyloidogenic catabolic pathways. The sequential cleavage of APP by the beta- and gamma-secretase activities, known as the amyloidogenic processing of APP, leads to the formation of the amyloid-beta peptide (Abeta). Abeta is the main constituent of the amyloid core of senile plaques, a typical hallmark of Alzheimer's disease. In addition to secretases, other cellular proteolytic activities, like the proteasome, might participate in the metabolism of APP. We investigated the consequence of proteasome inhibition on the amyloidogenic processing of human APP. CHO cells and primary cultures of rat cortical neurons expressing human APP or a protein corresponding to its beta-cleaved C-terminal fragment (C99) were treated with lactacystin, an irreversible inhibitor of the chymotrypsin-like activity of the proteasome. Lactacystin significantly decreased the level of Abeta produced from APP in both cellular models, whereas the production of Abeta from C99 was not affected. Lactacystin did not inhibit gamma-secretase activity but was found to inhibit the beta-cleavage of APP, leading to a proportional decrease in Abeta production. Although lactacystin did not inhibit the catalytic activity of recombinant BACE1, a decrease in neuronal beta-secretase activity was measured after treatment with lactacystin.
Kienlen-Campard
Pascal
P
Experimental Pharmacology Unit, FARL/UCL 54 10, Université Catholique de Louvain, Brussels, Belgium.
Feyt
Christine
C
Huysseune
Sandra
S
de Diesbach
Philippe
P
N'Kuli
Francisca
F
Courtoy
Pierre J
PJ
Octave
Jean-Noël
JN
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003470:Culture Media; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D003864:Depression, Chemical; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D003470:Culture Media; D015853:Cysteine Proteinase Inhibitors; D009419:Nerve Tissue Proteins; C067713:lactacystin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000111:Acetylcysteine