Clearly, more studies, such as large-scale genome epidemiology or in vitro study using human ES cell systems, are necessary to elaborate correlations between leptin V145E mutation and the severity of obese phenotype in humans. In addition, studies are required to gain further insights on how leptin mutations, not only this V145E mutation, but also other mutations identified in humans, affect the binding to and subsequent activation of leptin receptor. Finally, the V145E substitution in the N-terminus of helix D supplements the known mutations in human and mouse leptin and thereby offers novel mouse model for the study of human obesity syndrome. The presence of extracellular b-amyloid plaques in the brain is one of the pathological hallmarks of Alzheimer��s disease. Mounting evidence has demonstrated that aberrant zinc homeostasis is involved in the pathogenesis of AD. In the post-mortem AD brain, a marked accumulation of zinc is found in the Ab plaques. Since Ab peptide has zinc-binding sites, and zinc is the only physiologically available metal able to precipitate Ab, the Ibrutinib Src-bcr-Abl inhibitor abnormal enrichment of zinc in the AD brain indicates that zinc binding to Ab plays a role in the formation of amyloid plaques. Furthermore, zinc chelating agents, such as CX-4945 clioquinol and DP-109, that modulate brain zinc levels can inhibit the formation of amyloid plaques. In preliminary studies, CQ has shown some effects on cognition in AD patients. Thus, abnormal zinc homeostasis is believed to be a contributing factor leading to Ab aggregation, and alteration of zinc homeostasis is a potential therapeutic strategy for AD. The disruption of zinc homeostasis in the AD brain is associated with the aberrant distribution and altered expression of zincregulating metalloproteins, such as metallothionein, zinc transporters and divalent metal transporter 1. We have reported that high levels of ZnT1, 3-7 and DMT1 proteins are located in the degenerating neurites in or around the Ab-positive plaques associated with human AD and the APP/presenilin 1 transgenic mouse brain. Significant alterations in the expression levels of ZnT1, 4, and 6 have been detected in AD postmortem brain specimens. Genetic abolition of ZnT3 results in disappearance of zinc ions in the synaptic vesicles, and leads to an age-dependent deficit in learning and memory in ZnT3 knockout mice. Most interestingly, a markedly reduced plaque load and less insoluble Ab have been observed in ZnT3 knockout plus APP overexpressed mouse brain, suggesting a role of synaptic zinc in Ab generation and aggregation. Furthermore, in vitro studies have shown that both APP and its proteolytic product Ab contain zinc binding domains. However, the involvement of zinc in APP processing and Ab deposition has not been well established in AD transgenic models in vivo.