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Beta-secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice


Year of Publication:
Contact PI Name:
Jordan Tang
Contact PI Affiliation:
Protein Studies Program, Oklahoma Medical Research Foundation, and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
Wan-Pin Chang, Xiangping Huang, Deborah Downs, John R. Cirrito, Gerald Koelsch, David M. Holtzman, Arun K. Ghosh
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Association
Study Goal and Principal Findings:

In this study the authors provide the first direct experimental evidence that the treatment of Tg2576 transgenic mice with an inhibitor of beta-secretase, GRL-8234, rescues the age-related cognitive decline. The authors demonstrated that the injected GRL-8234 effectively enters the brain and rapidly decreases soluble Abeta in the brain of Tg2576 mice. The rescue of cognition, which was observed only after long-term inhibitor treatment ranging from 5 to 7.5 mo, was associated with a decrease of brain beta amyloid- plaque load. In addition the authors found no accumulation of APP after several months of inhibitor treatment. These observations substantiate the idea that Abeta accumulation plays a major role in the cognitive decline of Tg2576 mice and support the concept of Abeta reduction therapy as a treatment of AD.

Therapeutic Agent

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

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
B6/SJL mixed background

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
Y Maze
beta Amyloid Deposits
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
ISF-beta Amyloid Peptide 40
Amyloid Precursor Protein (APP) Metabolites
Brain-beta Amyloid Oligomers
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
Drug Concentration-Brain
Drug Concentration-Plasma
Area Under the Curve (AUC)
Brain/Plasma Ratio
Target Engagement (Reduction beta Amyloid Peptide 40-Brain)
Target Engagement (Reduction beta Amyloid Peptide 42-Brain)
Body Weight
Motor Function