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Licensed Unlicensed Requires Authentication Published by De Gruyter January 29, 2007

Cysteine protease inhibitors effectively reduce in vivo levels of brain β-amyloid related to Alzheimer's disease

Vivian Hook, Mark Kindy and Gregory Hook
From the journal

Abstract

Abnormal accumulation of neurotoxic β-amyloid peptides (Aβ) in brain represents a key factor in the progression of Alzheimer's disease (AD). Identification of small molecules that effectively reduce brain levels of Aβ is important for development of Aβ-lowering agents for AD. In this study, we demonstrate that in vivo Aβ levels in brain are significantly reduced by the cysteine protease inhibitor E64d and the related CA074Me inhibitor, which inhibits cathepsin B. Direct infusion of these inhibitors into brains of guinea pigs resulted in reduced levels of Aβ by 50–70% after 30 days of treatment. Substantial decreases in Aβ also occurred after only 7 days of inhibitor infusion, with a reduction in both Aβ40 and Aβ42 peptide forms. A prominent decrease in Aβ peptides was observed in brain synaptosomal nerve terminal preparations after CA074Me treatment. Analyses of APP-derived proteolytic fragments showed that CA074Me reduced brain levels of the CTFβ fragment, and increased amounts of the sAPPα fragment. These results suggest that CA074Me inhibits Aβ production by modulating APP processing. Animals appeared healthy after treatment with these inhibitors. These results, showing highly effective in vivo decreases in brain Aβ levels by these cysteine protease inhibitors, indicate the feasibility of using related compounds for lowering Aβ in AD.

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Corresponding author

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Published Online: 2007-01-29
Published in Print: 2007-02-01

©2007 by Walter de Gruyter Berlin New York

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