Cysteine protease inhibitors reduce brain β-amyloid and β-secretase activity in vivo and are potential Alzheimer's disease therapeutics

beta-Secretase inhibitors that lower brain beta-amyloid peptides (A beta) are likely to be effective for treating Alzheimer's disease (AD). Irreversible epoxysuccinyl cysteine protease inhibitors are known to reduce brain A beta and beta-secretase activity in the guinea pig model of human A beta production. In this study, acetyl-L-leucyl-L-valyl-L-lysinal (Ac-LVK-CHO) is also shown to significantly reduce brain A beta and beta-secretase activity and brain A beta in the same model. Ac-LVK-CHO is structurally distinct from the epoxysuccinyl inhibitors and is a reversible cysteine protease inhibitor. The results suggest that cysteine protease inhibitors generally, and reversible cysteine protease inhibitors specifically, have potential for development as AD therapeutics.