Myricetin: A Naturally Occurring Regulator of Metal-Induced Amyloid-β Aggregation and Neurotoxicity

No AbstractPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/84385/1/1198_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/84385/2/cbic_201000790_sm_miscellaneous_information.pd

Recent Development of Bifunctional Small Molecules to Study Metal-Amyloid-β Species in Alzheimer's Disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease related to the deposition of aggregated amyloid-β (Aβ) peptides in the brain. It has been proposed that metal ion dyshomeostasis and miscompartmentalization contribute to AD progression, especially as metal ions (e.g., Cu(II) and Zn(II)) found in Aβ plaques of the diseased brain can bind to Aβ and be linked to aggregation and neurotoxicity. The role of metal ions in AD pathogenesis, however, is uncertain. To accelerate understanding in this area and contribute to therapeutic development, recent efforts to devise suitable chemical reagents that can target metal ions associated with Aβ have been made using rational structure-based design that combines two functions (metal chelation and Aβ interaction) in the same molecule. This paper presents bifunctional compounds developed by two different design strategies (linkage or incorporation) and discusses progress in their applications as chemical tools and/or potential therapeutics

Survival in amoeba: a major selection pressure on the presence of bacterial copper and zinc resistance determinants?: identification of a "copper pathogenicity island"

The presence of metal resistance determinants in bacteria usually is attributed to geological or anthropogenic metal contamination in different environments or associated with the use of antimicrobial metals in human healthcare or in agriculture. While this is certainly true, we hypothesize that protozoan predation and macrophage killing are also responsible for selection of copper/zinc resistance genes in bacteria. In this review, we outline evidence supporting this hypothesis, as well as highlight the correlation between metal resistance and pathogenicity in bacteria. In addition, we introduce and characterize the "copper pathogenicity island" identified in Escherichia coli and Salmonella strains isolated from copper- and zinc-fed Danish pigs

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

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.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/96021/1/jbraymer_1.pd

Characterization of pyridinylimine and pyridinylmethylamine derivatives and their corresponding metal complexese

Bidentate pyridinylimine (L1-a and L1-b) and pyridinylmethylamine (L2-a and L2-b) derivatives have recently received attention due to their potential use as chemical reagants that can target metal-associated amyloid-?? (A??) species and modulate metal-induced A?? aggregation and neurotoxicity in vitro and in living cells. Herein, we report the characterization of these bidentate ligands and their corresponding metal complexes by X-ray crystallography and spectroscopic methods, including UV-Vis spectroscopy (UV-Vis), nuclear magnetic resonance spectroscopy (NMR), and Fourier transform infrared spectroscopy (FT-IR). Our studies presented how the different structural moieties of ligand frameworks (L1-a, L1-b, L2-a, and L2-b), in addition to effects of metal binding, contribute to variations in structure and chemical environments of the ligands and their corresponding metal complexes.close8