Compelling evidence has indicated that dyshomeostasis of biometals (Fe, Cu, Zn) and oxidative stress are neurochemical factors that participate in Abeta amyloid pathology of AD. The candidates found in vitro that they could promote aggregation and oxidative modifications of Abeta peptides, and recent reports show that amyloid plaques in post-mortem brain tissue of AD are markedly enriched in these biometals. Conversely, removal of these metals with chelators from post-mortem AD brain specimen causes the Abeta amyloid plaques to dissolve. More recently, the candidates discovered that novel redox interactions between Abeta and Cu(II), and to a lesser extent, Fe(III), engender production of reduced metal ions, Cu(I) and Fe(II), and the consequent generation of reactive oxygen species (ROS)-hydrogen peroxide (H2O2) and hydroxyl radical (OH). These abnormal interactions may lead to the brain oxidation damage that is observed in AD. Moreover, studies have also shown that H2O2 mediates Abeta cellular toxicity, enhances cellular APP expression, and heightens Abeta production, implicating a vicious cycle between Abeta amyloidosis and oxidative stress. Hence, the candidates hypothesize: Dysregulation of biometals (Fe, Cu, and Zn) and oxidative stress potentiate AD pathology. To test the hypothesis, the applicants plan to: (i) assess the impact of dietary metal supplementation with Fe, Cu and Zn, as well as oxidative stress induced by the dietary thiamine deficiency, upon Abeta amyloid pathology and non-amyloid pathology using APP2576 mice; (ii) to evaluate effects of redox-activ Fe and Cu on Abeta neurotoxicity using primary neuronal culture; (iii) to determine cerebral H2O2 levels accompanying Abeta amyloidosis using in vivo microdialysis. These data will advance our understanding of in vivo biochemical roles of biometal dyshomeostasis and oxidative stress in AD pathology, and provide a firm scientific base for understanding the potential of metal chelation and antioxidant therapies for AD.
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