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

Abstract

Rationale: 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.

Objectives: The effects of administration of two acetylcholinesterase inhibitors, physostigmine and donepezil, on Abeta plaque formation and memory-related behaviors were investigated in the Tg2576-transgenic mouse model of AD. At 9-10 months of age, Tg2576-transgenic [Tg(+)] mice develop Abeta plaques and impairments on paradigms related to learning and memory as compared to transgene-negative [Tg(-)] mice.

Methods: Beginning at 9 months of age, increasing doses of physostigmine (0.03, 0.1, and 0.3 mg/kg), donepezil (0.1, 0.3, and 1.0 mg/kg), or saline were administered over 6 weeks to cohorts of Tg(+) and Tg(-) mice. Performance on tests of spatial reversal learning and fear conditioning was evaluated at each drug dose throughout the period of drug administration. After drug administration was completed, the animals were sacrificed and Abeta plaque number was quantified.

Results: Administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg(+) mice so that their behaviors became more similar to 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.

Conclusions: These studies suggest that acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice without necessarily altering the deposition of Abeta plaques. Tg2576 mice may be useful as an animal model to further investigate the mechanisms by which aceytlcholinesterase inhibitors improve cognitive deficits in patients with AD.

Figure 1.

Behavioral performance in animals administered physostigmine (n = 5 Tg(+) and 6 Tg(-)) or saline (n = 5 Tg(+) and 5 Tg(-)). The effect of dose/time on acquisition of the spatial learning paradigm (panel a) and reversal learning (panel b) was not significant, nor were there any significant interactions between dose/time x APP status for these measures (see text for statistics). However, there was a significant effect of dose/time, and a significant interaction between dose/time and APP status, on the capacity for contextual memory (panel c). The effect of dose/time, and the interaction between dose/time and APP status, on the measurement of cued memory was not significant (panel d). Significant post-hoc between-group differences in groups of Tg(+) or Tg(-) mice administered a particular drug dose versus saline are indicated as follows: * - p<.05, **- p<.01, *** p<.001.

Figure 2.

Behavioral performance in animals administered donepezil (n = 6 Tg(+) and 5 Tg(-)) or saline (n = 5 Tg(+) and 5 Tg(-)). The effect of dose/time, and the interaction between dose/time and APP status, was significant on acquisition of the spatial learning paradigm (panel A), but not on reversal learning (panel b) (see text for statistics). Similarly, the effect of dose/time on the measurement of contextual memory (panel c) and cued memory (panel d), as well as the interaction between dose/time and APP status on these measures was not significant. Significant post-hoc between-group differences in groups of Tg(+) or Tg(-) mice administered a particular drug dose versus saline are indicated as follows: * - p<.05, **- p<.01, *** p<.001.

Figure 3.

Aß plaque deposition in Tg(+) mice treated with physostigmine or donepezil (n= 5-7 per drug group). The effects of drug condition on the total number of Aß-amyloid plaques (panel a) and on the percentage of cortex and hippocampus occupied by Aß-immunoreactive plaques (panel b) were not significant.