In the present study, we extended our experiments to examine whether chronic intake of water containing a high level of zinc accelerates Ab deposition and APP cleavage in APP/PS1 mouse brain. We found that a high level of dietary zinc could cause cognition dysfunction and enhance the aggregation of Ab. Furthermore, we found that a high level of zinc also enhanced Ab generation through altering the expression Reversine Aurora Kinase inhibitor levels of APP and APP cleavage enzymes in vivo and in vitro. Our data support the possibility that dietary zinc overload has the potential to be a contributing factor to the pathophysiology of AD. Both APP and its proteolytic byproduct Ab, which play central roles in senile plaque formation in the R428 1037624-75-1 pathogenesis of AD, are zinc-containing metalloproteins that contain zinc-binding domains. Therefore, it is rational to speculate that zinc overload may be involved in APP expression, Ab generation and aggregation. In the present study, involving treatment with a high level of zinc in the drinking water of APP/PS1 mice, we found that mice fed a high zinc diet exhibited spatial learning impairments as shown by Morris water maze tests. Apart for body weight loss, fur color changes, raised serum and brain zinc levels, and a high zinc content in the drinking water resulted in no other overt signs of toxicity such as general behavioral and neurological changes during the entire observation period which our model mice were given a high zinc diet. This is in agreement with previous reports showing that there was no serious toxicity in C57BL/6 mice after chronic zinc treatment at the same dose. Thus, we further evaluated the effects of a chronic high dietary zinc intake on accumulation of Ab deposits, as well as APP expression and cleavage in the APP/PS1 transgenic mouse brain. We and others have reported that zinc is highly concentrated in amyloid plaques in human postmortem brain samples and in AD transgenic mouse brains. Here, we found that a high intake of dietary zinc resulted in an increase in zinc-containing plaques in APP/PS1 transgenic mice. Coincident with the AMG results, Ab immunohistochemical analyses demonstrated that there was an increased Ab burden in transgenic mice fed a high zinc diet. Since the small peptide Ab possesses selective high- and low-affinity zinc binding sites, and zinc at a concentration of 300 nM can rapidly destabilize Ab and result in fibril formation, it is likely that an overload of brain zinc increases Ab binding and, hence, enhances Ab aggregation and plaque formation in the brain after chronic administration of a high zinc diet. Zinc is toxic and, besides its physiological roles, it is involved in neuronal and glial death through activation of multiple intracellular pathways leading to necrotic, apoptotic and autophagic neuronal death.