Alzheimer's Disease:correlation of the suppression of β-Amyloid peptide secretion from cultured cells with inhibition of the chymotrypsin-like activity of the proteasome

Christie, G. and Markwell, R. E. and Gray, C. W. and Smith, L. and Godfrey, F. and Mansfield, F. and Wadsworth, H. and King, R. and McLaughlin, M. and Cooper, D. G. and Ward, R. V. and Howlett, D. R. and Hartmann, T. and Lichtenthaler, S. F. and Beyreuther, K. and Underwood, J. and Gribble, S. K. and Cappai, R. and Masters, C. L. and Tamaoka, A. and Gardner,, R. L. and Rivett, A. J. and Karran, E. H. and Allsop, David (1999) Alzheimer's Disease:correlation of the suppression of β-Amyloid peptide secretion from cultured cells with inhibition of the chymotrypsin-like activity of the proteasome. Journal of Neurochemistry, 73 (1). pp. 195-204. ISSN 0022-3042

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 β-amyloid peptide (Aβ) from cells. To evaluate more fully the role of the proteasome in this process, we have tested the effects on Aβ 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 β-amyloid production reported so far. We found that the ability of the peptide aldehyde and boronate inhibitors to suppress Aβ 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 Aβ formation.