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Dissecting the signaling pathway of nicotine-mediated neuroprotection in a mouse Alzheimer disease model

Qiang Liu^*,,1, Jie Zhang^*,,1, Hua Zhu, Chuan Qin, Qi Chen and Baolu Zhao^*,,||,2

^* State Key laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Academia Sinica, Beijing, China;

Graduate School of the Chinese Academy of Sciences, Beijing, China;

Institute of Laboratory Animal Science, Chinese Academy of Medical Science, Beijing, China;

The Salk Institute for Biological Studies, La Jolla, California, USA; and

^|| E-Institutes of NO and Inflammation, Shanghai University of Traditional Chinese Medicine. Shanghai, China

²Correspondence: Institute of Biophysics, Academia Sinica, 15 Datun Rd., Chaoyang District, Beijing 100101, China. E-mail: zhaobl{at}sun5.ibp.ac.cn

Nicotine has a therapeutic benefit in treating Alzheimer’s disease (AD). In the present study we show that nicotine decreases accumulation of ß-amyloid (Aß) 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 Aß 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.

Key Words: AD • 7nAChRs • signal pathway

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