To determine whether leaming deficits could be seen in transgenic mice expressing human amyloid precursor protein 770 (APP770). Methods Female heterozygous transgenic and nontransgenic mice aged 3, 6 and 9 months at the start of testing were used, with eight mice in each age group. All mice were subjected to various behavioral tasks including the Y-maze task and the Morris water maze. After behavioral testing, the mice were sacrificed, and their brain tissues were used for measuring the choline acetyltransferase (CHAT) activity. Results Nine-month-old transgenic mice exhibited spatial learming deficits in the Morris water maze and in spontaneous altemation in the Y-maze, compared with those of the age-matched non-transgenic mice. The behavioral changes accompanied a reduction of ChAT activity in the cortical and hippocampal regions of transgenic mice. On the other hand, these behavioral deficits were not observed in transgenic mice either at 3 or at 6 months of age, in which ChAT activity remained unchanged. Conclusions The present results show that the learning impairment observed in 9-month-old APP770 transgenic mice are accompanied by a decrease in cortical and hippocampal ChAT activities. This suggests that cholinergic deficits may be involved in the leaming impairment observed in these APP770 mice. This model will be a useful tool in advancing our understanding of the relationship between the cholinergic system and the cognitive deficits observed in Alzheimer's disease (AD). State Key Laboratory of Reproductive Biology (Li H), Department of Molecular Biology and Biotechnology (Shen XZ), Institute of Zoology, The Chinese Academy of Sciences, Beijing 100080, China