Metal Ions and Alzheimer’s Disease
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is the 4th leading cause of death in economically developed countries. It currently affects up to 4 million U.S. residents, but that number will increase substantially as the U.S. population ages. AD can be identified definitively only post-mortem and is diagnosed by the presence of amyloid plaques in brain tissue. These plaques contain fibrils composed of the 39-42 residue ß-amyloid (Aß) peptide. The underlying tenet of the “amyloid hypothesis” is that Aß is the causative agent in AD.
The role of metal ions in the etiology of AD is not well characterized on the molecular level; there are disparate views on the chemical nature and reactivity of the metal ion complexes both in the neuronal plaques that are the signature of disease and in soluble and fibrillar Aß complexes. Oxidative assault derived from redox-active metals (Fe and Cu) bound to Aß is believed to contribute to the neuronal damage that manifests itself in dementia. The chemical structure of any of the protein-metal ion complexes – with soluble Aß, fibrils, or plaques – has not been fully elucidated. Likewise, potential mechanisms of neurotoxicity induced by redox-active metal ions are not well-defined.
Delineating the structures of these complexes and the mechanism of metal ion reactivity are of compelling significance. Formation of the metal ion complexes can introduce altered structures and chemical properties of Aß so that an intimate understanding of the nature of these complexes is essential to understanding AD.
Transition Metal Mediated Guanine Oxidation in Condensed DNA
Using reverse micelles to artificially condense DNA and the well-studied reaction of guanine oxidation by ruthenium(III) polypyridyl complexes, the yields and rates of guanine radicalformation measured with condensed DNA are compared to those measured for the same process in dilute aqueous solution. The effect of the proximity of Ru3+ and guanine on the rates and yields of guanine oxidation can be differentiated from DNA packing effects by using short oligonucleotide duplexes vs. DNA that is 400-500 base pairs in length. Three different ruthenium polypyridyl complexes have been chosen for use in the proposed research; each of the complexes differs in its affinity for duplex DNA, thus providing information about the condensed DNA structure in the reverse micelles. The proposed experiments are direct and sensitive measures of guanine oxidation chemistry. The results of these studies will provide an improved model for the frequency and extent of oxidative DNA damage that occurs in vivo than previous guanine oxidation experiments conducted in dilute solution.
Development of Magnetic Materials using Biomolecular Scaffolds
The long-term goal of this project is to develop novel materials based on nucleic acids and transition metals.
Molecular magnets, which are discrete compounds or assemblies that display desirable magnetic properties (e.g. ferromagnetism),often take advantage of geometries provided by crystal packing forces, bridging metal ligands or polymeric structures.Rather than relying on crystal packing to induce unique magnetic properties, we propose utilization of existing DNA scaffolds to ligate transition metal ions. Our hypothesis is that incorporation of transition metals into well-ordered biomolecular structures will generate materials with novel properties. These materials are envisioned as performing functions distinct from those carried out by classical technologies.
The overall goal of the project is to develop novel materials using biological scaffolds in conjunction with paramagnetic species. While we aim to create new materials, our initial goal is to introduce transition metal ions into guanine quartets while maintaining the structural integrity of the DNA architecture and determining the magnetic interactions that may exist in the assemblies. In the future, we will develop a method to produce solids with long-range structural ordering of the individual molecular assemblies.
