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Nicotine attenuates ß-amyloid-induced neurotoxicity by regulating metal homeostasis

Jie Zhang^*,,¶, Qiang Liu^*,¶, Qi Chen, Nian-Qing Liu, Fu-Liang Li, Zhong-Bing Lu^*,¶, Chuan Qin, Hua Zhu, Yu-Ying Huang^¶, Wei He^|| and Bao-Lu Zhao^*,¶,1

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

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

Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics, Academia Sinica;

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

^|| Sychrotron Radiation Laboratory, Institute of High Energy Physics, Academia Sinica; and

^¶ Graduate School of the Chinese Academy of Sciences, Beijing, Peoples Republic of China

¹Correspondence: Institute of Biophysics, Academia Sinica, 15 Datun Rd., Chaoyang District, Beijing 100101, P.R. China. E-mail: zhaobl{at}sun5.ibp.ac.cn

ABSTRACT

Nicotine reduces ß-amyloidosis and has a beneficial effect against Alzheimer’s disease (AD), but the underlying mechanism is not clear. The abnormal interactions of ß-amyloid (Aß) with metal ions such as copper and zinc are implicated in the process of Aß deposition in AD brains. In the present study, we investigated the effect of nicotine on metal homeostasis in the hippocampus and cortex of APP^V717I (London mutant form of APP) transgenic mice. A significant reduction in the metal contents of copper and zinc in senile plaques and neuropil is observed after nicotine treatment. The densities of copper and zinc distributions in a subfield of the hippocampus CA1 region are also reduced after nicotine treatment. We further studied the mechanism of nicotine-mediated effect on metal homeostasis by using SH-SY5Y cells overexpressing the Swedish mutant form of human APP (APPsw). Nicotine treatment decreases the intracellular copper concentration and attenuates Aß-mediated neurotoxicity facilitated by the addition of copper, and these effects are independent of the activation of nicotinic acetylcholine-receptor. These data suggest that the effect of nicotine on reducing ß-amyloidosis is partly mediated by regulating metal homeostasis.—Zhang, J., Liu, Q., Chen, Q., Liu, N.-Q., Li, F.-L., Lu, Z.-B., Qin, C., Zhu, H., Huang, Y.-Y., He, W., and Zhao, B.-L. Nicotine attenuates ß-amyloid-induced neurotoxicity by regulating metal homeostasis.

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