NAPVSIPQ (NAP) is a small, active fragment of activity-dependent neuroprotective protein that has neuroprotective and memory enhancing properties at very low concentrations. Previous research demonstrated that 1-2 weeks of treatment provided memory enhancing effects in normal middle-aged and cholinergically lesioned rats. Improvement in cognitive performance was shown in 12-month-old C57Bl6/J mice after 10 days of oral treatment with D-NAP and D-SALLRSIPA. Additionally, NAP-related cognitive benefits on spatial memory were observed in a 3xTg Alzheimer mouse model after 6 months of chronic administration at a moderate stage of disease. In this study, the potential memory enhancing effect of NAP was investigated using the APP23 transgenic mouse model for Alzheimer's disease. Twelve-month-old male heterozygous APP23 mice and their wild-type control littermates were intraperitoneally injected with 0.3 microg NAP/g body weight or with saline vehicle for 22 consecutive days. Cognitive performance training in the Morris Water Maze (MWM) started on day 8 of treatment. The internal validity of our study was demonstrated by the fact that the APP23 mice performed significantly worse in the MWM than wild-type animals. Treatment with NAP, however, did not exert any significant effects on MWM performance. Although we failed to show significant memory enhancing effects in this study, NAP might be a promising peptide for disease-modifying therapy in neurodegenerative disease, but short-term effects are probably not to be expected. Also, most likely, treatment should start in an early stage, i.e. before full-blown pathology is eminent, and the necessary treatment period should enclose several months.