Amyloid Beta and Transition Metals: Structure and Reactivity

Project Summary

The diagnosis of Alzheimer's disease (AD) is determined by the appearance of neuro-fibrillary tangles and amyloid plaques in brain tissue. Amyloid plaques are composed of repeating units of the protein amyloid-beta (Aß). While the global structure of amyloid plaques has to a great extent been revealed, local structural factors are not well understood. Transition metal ions like copper, zinc and iron have been observed to both increase and decrease the rate of Aß aggregation in vitro. The transition metals may not play an exclusively structural role in the biochemistry of Aß. The levels of copper ions are increased in the vicinity of amyloid plaques, yet decreased overall in AD-affected brains, implying that transition metal ion homeostasis is affected during the progression of the disease. The finding that transition metal ion levels in brains from AD patients are different from the levels in control samples has led researchers to investigate metal ion involvement in the neurotoxic events. In the presence of Aß in a test tube, some transition metals trap dioxygen to generate species that could potentially lead to neurodamage. The purpose of this study is to investigate the chemistry of metal ions in amyloid plaque neurotoxicity. Because a drug that binds metal ion has already been shown to dissolve amyloid plaques in vitro, the results could be helpful in designing new therapeutic strategies. If the mechanisms of the role of metal ions with Aß can be understood, Dr. Szalai's team may be able to provide a promising new direction for drug design.