Acad Sinica, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China
; Salk Inst Biol Studies, La Jolla, CA 92037 USA
; Acad Sinica, Lab Nucl Analyt Tech, Inst High Energy Phys, Beijing 100101, Peoples R China
; Chinese Acad Med Sci, Inst Lab Anim Sci, Beijing 100037, Peoples R China
; Acad Sinica, Inst High Energy Phys, Sychrotron Radiat Lab, Beijing 100101, Peoples R China
; Chinese Acad Sci, Grad Sch, Beijing, Peoples R China
Nicotine reduces beta-amyloidosis and has a beneficial effect against Alzheimer's disease (AD), but the underlying mechanism is not clear. The abnormal interactions of beta-amyloid (A beta) with metal ions such as copper and zinc are implicated in the process of A beta 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 A beta-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 beta-amyloidosis is partly mediated by regulating metal homeostasis.