AIM We have demonstrated for the first time that nobiletin (NB) from citrus peels improves memory impairment in Alzheimers disease (AD) model animals.METHODS AND RESULTS Amyloid precursor protein (APP) transgenic (Tg) mice have been extensively used as an indispensable AD model animal.NB markedly improved memory deficits and caused a great decrease in the Aβ burden and plaques in the hippocampus in Tg mice.On the other hand, olfactory-bulbe etomized (OBX) mice have been widely utilized as a useful paradigm that shares some major clinical features of AD.NB rescued gready memory deficits accompanied by the OBX-indused decrease in the density of AChE-positive fibers.In cultured hippocampal neurons Aβ inhibited both CREB phosphorylation and CRE-mediated transcription stimulated by glutamate.NB antagonized both of the inhibitory effects of Aβ.CONCLUSION These results suggest that NB decreases the Aβ burden and plaques in the hippocampus and reverses the Aβ-induced inhibition of CREB-mediated signaling coupled with CRE-dependent transcription, resulting in improvement of learning impairment.It is also suggested that nobiletin has become a useful natural compound for functional food development for AD.