Nicotine has a therapeutic benefit in treating Alzheimer’s disease (AD). In the present study we show that nicotine decreases accumulation of -amyloid (A) in the cortex and hippocampus of APP (V717I) transgenic mice. Nicotine prevents activation of NF-B and c-Myc by inhibiting the activation of MAP kinases (MAPKs). As a result, the activity of inducible NOS and the production of NO are down-regulated. RNA interference experiments show that the above nicotine-mediated process requires 7 nAChR. Nicotine decreases A via the activation of 7nAChRs through MAPK, NF-B, and c-myc pathways. Nicotine also inhibits apoptosis and cell cycle progression in this mouse line. The dissected signaling pathway of nicotine-mediated neuroprotection in the present study provides a mechanistic basis for the potential development of drug targets for treating AD.--Liu, Q., Zhang, J., Zhu, H., Qin, C., Chen, Q., Zhao, B. Dissecting the signaling pathway of nicotine-mediated neuroprotection in a mouse Alzheimer disease model.