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

Biol Chem. 2007 Feb;388(2):247-52. doi: 10.1515/BC.2007.027.


Abnormal accumulation of neurotoxic beta-amyloid peptides (Abeta) in brain represents a key factor in the progression of Alzheimer's disease (AD). Identification of small molecules that effectively reduce brain levels of Abeta is important for development of Abeta-lowering agents for AD. In this study, we demonstrate that in vivo Abeta 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 Abeta by 50-70% after 30 days of treatment. Substantial decreases in Abeta also occurred after only 7 days of inhibitor infusion, with a reduction in both Abeta40 and Abeta42 peptide forms. A prominent decrease in Abeta 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 CTFbeta fragment, and increased amounts of the sAPPalpha fragment. These results suggest that CA074Me inhibits Abeta production by modulating APP processing. Animals appeared healthy after treatment with these inhibitors. These results, showing highly effective in vivo decreases in brain Abeta levels by these cysteine protease inhibitors, indicate the feasibility of using related compounds for lowering Abeta in AD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / drug effects
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / drug effects*
  • Brain / metabolism*
  • Cathepsin B / antagonists & inhibitors
  • Cysteine Endopeptidases / drug effects*
  • Cysteine Endopeptidases / isolation & purification
  • Dipeptides / administration & dosage*
  • Dipeptides / pharmacology
  • Guinea Pigs
  • Leucine / administration & dosage
  • Leucine / analogs & derivatives*
  • Leucine / pharmacology
  • Molecular Weight
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / pharmacology
  • Synaptosomes / chemistry


  • Amyloid beta-Peptides
  • CA 074 methyl ester
  • Dipeptides
  • Protease Inhibitors
  • Cysteine Endopeptidases
  • Cathepsin B
  • Leucine
  • aloxistatin