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

Bibliographic

Year of Publication: 
2008
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
Co-Authors: 
Mark Kindy, Gregory Hook
Primary Reference (PubMED ID): 
Funding Source:
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:
Therapy Type:

Animal Model

Model Information: 
Species:
Model Type:
Strain/Genetic Background: 
C57BL/6
Species:
Model Type:
Strain/Genetic Background: 
C57BL/6

Experimental Design

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

Outcomes

Outcomes: 
Outcome MeasuredOutcome Parameters
Behavioral
  • Morris Water Maze
  • Histopathology
  • beta amyloid load
  • Biochemical
  • Brain-beta amyloid peptide 40
  • Brain-beta amyloid peptide 42
  • APP-CTF99 (CTF beta)
  • sAPP alpha
  • BACE1 Activity