Alzheimer's disease: correlation of the suppression of beta-amyloid peptide secretion from cultured cells with inhibition of the chymotrypsin-like activity of the proteasome.
Peptide aldehyde inhibitors of the chymotrypsin-like activity of the proteasome (CLIP) such as N-acetyl-Leu-Leu-Nle-H (or ALLN) have been shown previously to inhibit the secretion of beta-amyloid peptide (A beta) from cells. To evaluate more fully the role of the proteasome in this process, we have tested the effects on A beta formation of a much wider range of peptide-based inhibitors of CLIP than published previously. The inhibitors tested included several peptide boronates, some of which proved to be the most potent peptide-based inhibitors of beta-amyloid production reported so far. We found that the ability of the peptide aldehyde and boronate inhibitors to suppress A beta formation from cells correlated extremely well with their potency as CLIP inhibitors. Thus, we conclude that the proteasome may be involved either directly or indirectly in A beta formation.
Christie
G
G
SmithKline Beecham Pharmaceuticals, Harlow, Essex, England, UK.
Markwell
R E
RE
Gray
C W
CW
Smith
L
L
Godfrey
F
F
Mansfield
F
F
Wadsworth
H
H
King
R
R
McLaughlin
M
M
Cooper
D G
DG
Ward
R V
RV
Howlett
D R
DR
Hartmann
T
T
Lichtenthaler
S F
SF
Beyreuther
K
K
Underwood
J
J
Gribble
S K
SK
Cappai
R
R
Masters
C L
CL
Tamaoka
A
A
Gardner
R L
RL
Rivett
A J
AJ
Karran
E H
EH
Allsop
D
D
D000447:Aldehydes / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology; D002460:Cell Line; D002918:Chymotrypsin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism*; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D014162:Transfection
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001897:Boronic Acids; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D002918:Chymotrypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex