Understanding the Roles of Metal Ions in the Fate of Reactive Oxygen Species and in Alzheimer’s Disease.

Abstract

Biologically relevant metal ions play crucial roles in metabolic regulation and cellular function throughout nature and in the human body. An important regulatory mechanism is control of reactive oxygen species (ROS). The most abundant ROS molecule is hydrogen peroxide (H2O2), which is detoxified by heme enzymes called catalases. The breakdown of H2O2 by catalases has been proposed to involve a high-valent oxoiron(IV) porphyrin π-cation radical. While the mechanism is not fully understood, high-valent oxoiron(IV) species from other enzymes that possess different coordination to the metal center (nonheme) have not been previously reported to react with H2O2. Work carried out in this thesis project has shown that both synthetic heme and nonheme high-valent oxoiron(IV) complexes can react with H2O2 directly, which gives potential insight into ROS production and detoxification in vivo. When metal and ROS homeostasis is disrupted, especially in the brain, it is believed to have severe consequences resulting in various diseases, such as Alzheimer’s disease (AD). AD is the most prevalent form of dementia and is characterized by the build up of amyloid-β (Aβ) peptide aggregates that are believed to contribute to AD pathology. These aggregates have also been shown to be co-localized with metals, which can facilitate aggregation of Aβ and neurotoxicity through production of ROS in vitro. Although tremendous effort has been put forth to uncover the etiology of AD, it is still unknown what factors promote neurodegeneration in the brain, in addition to how metal-amyloid-β (metal-Aβ) species contribute to AD. To provide a handle on studying metal-associated Aβ, bifunctional small molecules that can probe the relationship between metal ions and Aβ have been developed and studied via various spectroscopic methods. These compounds are capable of modulating several modes of metal-Aβ reactivity and show promise for the continued development of new chemical reagents for investigating metal-Aβ chemistry and biology in AD.