Interestingly, a recent study involving APP/PS1 mice fed a zinc-deficient diet has shown that such a diet increases the plaque volume but does not alter the total plaque number in the brain. Chronic high zinc- or copper-treated mice overexpress APP-C100, which contains Ab but not the N-terminal zinc and copper binding domain of APP, resulting in reduced soluble Ab levels but with no changes in the total Ab levels in the brain. It has also been reported that exposure to copper and, presumably, a mixture of other metals in drinking water results in enhanced Ab deposition in the brains of rabbits fed a high cholesterol diet. Alain Boom and colleagues showed that 100 mM zinc induced the appearance known to be associated with increased tau phosphorylation, suggesting that zinc plays a considerable role in the development of tau pathology associated to Alzheimer��s disease. On the other hand, some reports have shown the protective effects of low micromolar GDC-0879 inquirer concentrations of zinc against Ab cytotoxicity. So far, the role of zinc in AD remains debatable. Both high and low zinc could play a harmful role. Whether or not to supply zinc and what the suitable dose range should be are topics worthy of future research on AD. Taking these findings together with the present evidence that high-dose zinc treatment leads to enhanced amyloidogenic APP cleavage and Ab aggregation in the APP/ PS1 mouse brain and APPsw overexpressing cells, it can be Y-27632 side effects concluded that disturbed metal homeostasis is involved in multiple steps of APP processing and Ab deposition by a series of complicated mechanisms. In summary, the present study provides evidence that chronic exposure to high zinc levels in drinking water leads to an increase in APP expression, amyloidogenic APP cleavage and Ab deposition in the APP/PS1 transgenic mouse brain. The present data, together with previous reports, suggest that excess zinc exposure could be a risk factor for AD pathological processes, and corrections of metal abnormalities in the brain are beneficial strategies for AD prevention and therapy. Morris water maze tests were carried out as previously described with few modifications, using a circular tank, equipped with a digital pick-up camera to monitor the animal behavior and a computer program for data analysis.