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.