Alzheimer's Disease |
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Authors: | G. Christie,R. E. Markwell,C. W. Gray,L. Smith,F. Godfrey,F. Mansfield,H. Wadsworth,R. King,M. McLaughlin,D. G. Cooper,R. V. Ward,D. R. Howlett,T. Hartmann,S. F. Lichtenthaler,K. Beyreuther,J. Underwood,S. K. Gribble,R. Cappai,C. L. Masters,A. Tamaoka,R. L. Gardner,A. J. Rivett,E. H. Karran,& D. Allsop |
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Affiliation: | SmithKline Beecham Pharmaceuticals, Harlow, Essex, England, UK. |
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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. |
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Keywords: | Alzheimer's disease Amyloid β-Amyloid peptide Proteasome Inhibitor. |
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