Inhibitors of Cathepsin B Improve Memory and Reduce β-Amyloid in Transgenic Alzheimer Disease Mice Expressing the Wild-type, but Not the Swedish Mutant, β-Secretase Site of the Amyloid Precursor Protein

Vivian Y.H. Hook,Mark Kindy,Gregory Hook

doi:10.1074/jbc.m708362200

Vivian Y.H. Hook, Mark Kindy + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m708362200

Copy DOI

Abstract

Elucidation of Abeta-lowering agents that inhibit processing of the wild-type (WT) beta-secretase amyloid precursor protein (APP) site, present in most Alzheimer disease (AD) patients, is a logical approach for improving memory deficit in AD. The cysteine protease inhibitors CA074Me and E64d were selected by inhibition of beta-secretase activity in regulated secretory vesicles that produce beta-amyloid (Abeta). The regulated secretory vesicle activity, represented by cathepsin B, selectively cleaves the WT beta-secretase site but not the rare Swedish mutant beta-secretase site. In vivo treatment of London APP mice, expressing the WT beta-secretase site, with these inhibitors resulted in substantial improvement in memory deficit assessed by the Morris water maze test. After inhibitor treatment, the improved memory function was accompanied by reduced amyloid plaque load, decreased Abeta40 and Abeta42, and reduced C-terminal beta-secretase fragment derived from APP by beta-secretase. However, the inhibitors had no effects on any of these parameters in mice expressing the Swedish mutant beta-secretase site of APP. The notable efficacy of these inhibitors to improve memory and reduce Abeta in an AD animal model expressing the WT beta-secretase APP site present in the majority of AD patients provides support for CA074Me and E64d inhibitors as potential AD therapeutic agents.

Highlights

Of mutant forms of human amyloid precursor protein (APP) in mouse models of Alzheimer disease (AD) results in increased A␤ and amyloid plaques in brain, with memory deficits that resemble AD [2, 3, 5,6,7]
Cathepsin B Inhibitors for Alzheimer Disease icant improvement in memory deficit, reduced amyloid plaque load in brain, reduced levels of A␤40 and A␤42 in brain, and reduced C-terminal ␤-secretase fragment (CTF␤) derived from APP by ␤-secretase when compared with untreated control animals. These cysteine protease inhibitors had no effect on any of these parameters in mice expressing the Swe mutant ␤-secretase site of APP. These results show that these cysteine protease inhibitors are efficacious for improving memory deficit in an AD mouse model representative of the majority of AD patients who express the WT ␤-secretase site of APP
Results found that the mean percentage of tissue area of amyloid plaques for the control, CA074Me-treated, and E64d-treated animals was 0.50, 0.22, 0.21% of the tissue area, respectively. These data demonstrate a significant 55% reduction in amyloid plaque load by the CA074Me and E64d inhibitors. These results demonstrate that the significant reduction of amyloid plaque by about one-half is sufficient to result in improved “memory deficit” after treatment of London APP mice with CA074Me or E64d cysteine protease inhibitors

Summary

Introduction

Of mutant forms of human amyloid precursor protein (APP) in mouse models of AD results in increased A␤ and amyloid plaques in brain, with memory deficits that resemble AD [2, 3, 5,6,7] Such studies demonstrate that overproduction of A␤ peptides participates as a major factor in the development of AD. Many previous studies of ␤-secretase have utilized substrates containing the Swe mutant ␤-secretase site (10 –14) expressed in one extended family [15], it is most relevant to study proteolytic cleavage of the WT ␤-secretase site expressed in the major portion of the AD population. Results from this study showed that administration of CA074Me or E64d to the London APP mice resulted in signif-

Objectives

Results

Conclusion