Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein

The aim of this study was to determine the efficacy of the cathepsin B inhibitors, CA074Me or E64d, in ameliorating the AD-like neuropathological and behavioral characteristics in two AD mouse models. Administration of the inhibitors to London APP mice resulted in significant improvement in memory deficit, reduced beta-amyloid plaque load in brain, reduced levels of Abeta 40 and Abeta 42 in brain, and reduced C-terminal beta -secretase fragment (CTFbeta) derived from APP by beta -secretase when compared with untreated control animals. In contrast, these cysteine protease inhibitors had no effect on any of these parameters in mice expressing the Swe mutant beta-secretase site of APP, in Swedish/London APP mice. The authors suggest that the notable efficacy of these inhibitors to improve memory and reduce Aβ in an AD animal model expressing the WT β-secretase APP site present in the majority of AD patients provides support for CA074Me and E64d inhibitors as potential AD therapeutic agents.