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

Abnormal accumulation of neurotoxic beta-amyloid peptides (A beta) in brain represents a key factor in the Progression of Alzheimer's disease (AD). Identification of small molecules that effectively reduce brain levels of is important for development of A beta-lowering agents for AD. In this study, we demonstrate that in vivo A beta 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 A beta by 50-70% after 30 days of treatment. Substantial decreases in A beta also occurred after only 7 days of inhibitor infusion, with a reduction in both A beta 40 an A beta 42 peptide forms. A prominent decrease in A beta peptides was observed in brain synaptosomal nerve terminal preparations after CA074Me treatment. Analyses of APP-derived proteolytic fragments showed that CA07Me reduced brain levels of the CTF beta fragment, and increased amounts of the sAPP alpha fragment. These results suggest that CA074Me inhibits A beta production by modulating APP processing. Animals appeared healthy after treatment with these inhibitors. These results, showing highly effective in vivo decreases in brain A beta levels by these cysteine protease inhibitors, indicate the feasibility of using related compounds for lowering A beta in AD.