The elevated level of zinc in the AD brain is caused, at least partly, by the abnormal distribution and expression of zinc-regulating proteins such as ZnTs and DMT1. At an early stage of AD, the elevated brain zinc results in the formation of zinc-Ab complex, which is of some benefit in protecting against zinc toxicity. On the other hand, recent studies have shown that soluble Ab is a major BAY-60-7550 factor in neuronal and synaptic pathology, since it is more toxic than insoluble Ab. It is likely that the initial zinc-Ab complex and subsequent Ab aggregation inhibits Ab mediated neurotoxicity. However, it is worth noting that the initial zinc-Ab complex may serve as a seed for the process of Ab aggregation and plaque formation in the brain. Although it is still Tubulin Acetylation Inducer HDAC inhibitor debatable whether Ab aggregation mediated by interaction with zinc plays a role in reducing the toxicity of soluble Ab or whether the zinc-containing plaques themselves are toxic to neuronal cells, the interaction between Ab and zinc seems to be a critical factor for activating AD pathological processes. Nevertheless, our present data suggest that a high zinc intake leads to more zinc-Ab complex formation, accelerates Ab deposition and enhances the amyloid burden. Further studies are needed to elucidate the paradoxical role of zinc in plaque pathology. APP protein contains a novel zinc binding motif which is located between the cysteine-rich and negatively charged ectodomains. Besides its structural role, zinc may be involved in the function and metabolism of APP protein, and produce an even greater deposition of Ab. However, apart for several in vitro studies that tested the effects of zinc on APP processing, there are no detailed reports whether zinc binding to APP alters APP processing and Ab production in AD transgenic animal models. In the present study, we found that a high intake of dietary zinc significantly increases the expression levels of APP protein in APP/ PS1 transgenic mouse brain. We also found that high-dose zinc treatment results in reduced expression levels of ADAM10, but enhances the levels of BACE1 and PS1, resulting in increased secretion of sAPPb over sAPPa in the transgenic mouse brain. Further, consistent with our in vivo data, high zinc exposure suppresses a-secretase cleavage, but enhances b- and csecretase cleavage of APP and Ab generation in APPsw overexpressing cells. Thus, our in vivo and in vitro studies clearly show that high-dose zinc treatment enhances the amyloidogenic APP cleavage pathway and Ab secretion.