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 protea some (CLIP) such as N-acetyl-Leu-Leu-Nle-H (or ALLN) have been shown previo usly 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-bas ed inhibitors of CLIP than published previously. The inhibitors tested incl uded several peptide boronates, some of which proved to be the most potent peptide-based inhibitors of beta-amyloid production reported so far. We fou nd that the ability of the peptide aldehyde and boronate inhibitors to supp ress A beta formation from cells correlated extremely well with their poten cy as CLIP inhibitors. Thus, we conclude that the proteasome may be involve d either directly or indirectly in A beta formation.