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Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease


Year of Publication:
Contact PI Name:
John G. Csernansky
Contact PI Affiliation:
Departments of Psychiatry, Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA
Hongxin Dong, Cynthia A. Csernansky, Maureen V. Martin, Amy Bertchume, Dana Vallera
Primary Reference (PubMED ID):
Funding Source:
National Institute of Mental Health (NIMH)
Study Goal and Principal Findings:

Acetylcholinesterase inhibitors are widely used for the treatment of patients with Alzheimer’s disease (AD). However, the relationship between the capacity of such drugs to ameliorate the symptoms of AD and their ability to alter the underlying disease process is not well understood. Transgenic mice that overexpress the human form of amyloid precursor protein and develop deposits of beta-amyloid (Abeta)and behavioral deficits during adulthood are useful for investigating this question.

The principal aim of the study is to compare acetylcholinesterase inhibitors physostigmine and donepezil on Abeta plaque formation and memory-related behaviors in Tg2576 mice. Administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg2576 (Tg+) mice so that their behaviors became more similar to non-transgenic (Tg-)mice. However, administration of physostigmine and donepezil tended to improve cued memory and deficits in spatial learning in both Tg(+) and Tg(-) mice. Physostigmine administration demonstrated more prominent effects in improving contextual memory than donepezil, while donepezil was more effective than physostigmine in improving deficits in the acquisition of the spatial memory paradigm. Administration of neither drug altered the deposition of Abeta plaques. As expected, deficits in spatial learning and in both contextual and cued memory associated with a fear conditioning paradigm were present in Tg(+) mice as compared to Tg (-) mice. In the first phase of the analysis of the data, we found that administration of the two acetylcholinesterase inhibitors improved deficits in contextual memory in Tg(+) mice so that their behaviors became more similar to Tg(-) mice. However, we unexpectedly found that donepezil administration improved acquisition of the spatial memory task in Tg(-) mice. Overall, our findings are consistent with the cognition-enhancing effects of acetylcholinesterase inhibitors in AD patients, but the findings with donepezil in Tg(-) mice suggest that the cognition-enhancing effects of such drugs may not be limited to the dementia associated with AD. 

Therapeutic Agent

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

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic 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
Spatial Learning Task
Fear Conditioning Response
Shock Sensitivity
Motor Function
Locomotor Activity
beta Amyloid Load
beta Amyloid Deposits