title: 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.
abstract: 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.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Harlow, Essex, England, UK.
authors.forename: G
authors.initials: G
authors.lastname: Christie
authors.forename: R E
authors.initials: RE
authors.lastname: Markwell
authors.forename: C W
authors.initials: CW
authors.lastname: Gray
authors.forename: L
authors.initials: L
authors.lastname: Smith
authors.forename: F
authors.initials: F
authors.lastname: Godfrey
authors.forename: F
authors.initials: F
authors.lastname: Mansfield
authors.forename: H
authors.initials: H
authors.lastname: Wadsworth
authors.forename: R
authors.initials: R
authors.lastname: King
authors.forename: M
authors.initials: M
authors.lastname: McLaughlin
authors.forename: D G
authors.initials: DG
authors.lastname: Cooper
authors.forename: R V
authors.initials: RV
authors.lastname: Ward
authors.forename: D R
authors.initials: DR
authors.lastname: Howlett
authors.forename: T
authors.initials: T
authors.lastname: Hartmann
authors.forename: S F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.forename: K
authors.initials: K
authors.lastname: Beyreuther
authors.forename: J
authors.initials: J
authors.lastname: Underwood
authors.forename: S K
authors.initials: SK
authors.lastname: Gribble
authors.forename: R
authors.initials: R
authors.lastname: Cappai
authors.forename: C L
authors.initials: CL
authors.lastname: Masters
authors.forename: A
authors.initials: A
authors.lastname: Tamaoka
authors.forename: R L
authors.initials: RL
authors.lastname: Gardner
authors.forename: A J
authors.initials: AJ
authors.lastname: Rivett
authors.forename: E H
authors.initials: EH
authors.lastname: Karran
authors.forename: D
authors.initials: D
authors.lastname: Allsop
mesh_terms: 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
chemical_list: 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