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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


Year of Publication:
Contact PI Name:
Vivian Y. Hook
Contact PI Affiliation:
Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA
Mark Kindy, Gregory Hook
Primary Reference (PubMED ID):
Funding Source:
Applied Neurotechnology Inc.
National Institute on Aging (NIA)
Study Goal and Principal Findings:

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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Cathepsin B
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Cathepsin B

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Animal Model Notes:
See Lamb et al 1993 ( for development and characterization of the APPSweLon transgenic mouse model.

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
beta Amyloid Load
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
APP-CTF99 (CTF beta)
Soluble Amyloid Precursor Protein alpha (sAPP alpha)
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Activity