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Zinc,one of the most important trace elements,palys an critical role in synaptic transmission, learning and memory. Zinc disturbance is observed in aging brains with the decline of learning and memory ability. In the brains of patients with Alzheimer’s Disease (AD), zinc ions are concentrated in susceptible brain 1regions and promote the formation of senile plaque(SP). Strong evidences have shown that supplement of zinc could improve the brain development in children with zinc deficiency, however, it is unknown whether zinc supplement also benefits the brain health in normal children with no zinc deficiency. In the present study, mice fed with different doses of zinc were used to explore the effects of zinc intake in childhood on brain zinc homeostasis and the ability of learning and memory. Methods: Weaned ICR male mice(21 days) were treated with a low dose of zinc (66.2 mg/L ZnSO4.7H2O in drinking water, equivalent to 10mg zinc daily intake for children) or a high dose of zinc (ZnSO4.7H2O 265 mg/L in drinking water, equivalent to 40mg zinc daily intake for children) for 3 months,then a series of behavioral experiments were used to detect their learning and memory abilities. After the behaviour research, half of the mice in each group were sacrificed, the blood and brain tissues were obtained for the biochemic and immunohistochemistry detections, the other half mice were fed with standard diet and normal water until 20 months for further assays and detections. Results:⑴The serum zinc levels were significantly increased in mice treated with low dose of zinc for 3 months, while high dose of zinc intake does not increase the serum zinc level;⑵The levels of zinc in the hippocampus were decreased in both low and high dose zinc groups;⑶The levels of Zinc transporter 1(ZnT1) and Zinc transporter 4(ZnT4) were increased in two groups of mice fed with zinc,the level of Zinc transporter 3(ZnT3) was dramatically decreased in low dose zinc group;⑷Compared with normal control, mice fed with low dose of zinc showed better short memory and working memory, however, high level zinc intake induced decreased ability of short memory;⑸The AMPA receptor subunit GLUR2 and phosphorylated synapsin-1(active form) were significantly increased in low dose zinc group, while the protein levels of glutamate NR2A,NR2B subunits and GLUR2 were decreased in high dose zinc group. At the same time,the levels of synaptic proteins Munc18,PSD93 and PSD95, the active forms of synapsin-1, CaMKⅡ, extracellular signal-regulated kinase (ERK) and PKAα, and the total and phosphorylated nuclear transcription factor CREB were all significantly reduced in high dose zinc group;⑹Zinc exposure for 3 months resulted in tau hyperphosphorylation at multiple AD-like phosphorylation sites such as Ser396 and Ser404 in hippocampus;⑺In aging mice (20 months), high level zinc intake in young age resulted significantly increased total and phosphorylated tau, especially total tau in hippocampus,as well as decreased synapsin-1 level and decreased activie form of CaMKⅡ.Conclusions: Low dose of zinc supplementation could improve the learning and memory abilities in youth. On the contrary, exposure to high dose of zinc may induce brain zinc dys-homeostasis, downregulation of NR2A/NR2B, GLUR2 and synaptic associated proteins, and decreased learning and memory abilities. Effects of high level zinc intake in young age may persist until old age, it may induce AD-like tau phosphorylation and aggregation in aging. Thus low dose of zinc supplementation could help children to improve learning and memory capacity, but high level of zinc intake will impair the learning and memory and accelerate AD-like pathologic changes.
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