|Szalai Group Summer 2006|
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.
The following specific aims are being pursued:
(A) Develop a molecular-level model of Cu-containing Aß fibrils.
(B) Determine the mechanism through which Cu:Aß produces reactive oxygen species.
(C) Assess the neurotoxicity of Cu-loaded Aß.
Development of Novel Materials using Biomolecular Scaffolds
Self-assembled nanomaterials are an important component of nanotechnology development. Nanoscale materials should possess molecular properties inherent of the nanoscale realm, should self assemble, and provide emergence in which the properties of the sum differ from the properties of the individual parts. This project’s objective is to create bottom-to-top, self-assembling supramolecular structures suitable for nanoelectronics based on guanine-rich sequences that form a DNA structural element called a guanine quadruplex. Transmission of information through these materials will be accomplished by creating hybrid polymers containing DNA and transition metal complexes/ions. A potential application of these assemblies is in nanoscale magnetic/electronic devices used for display and data recording.
Objective #1 – To investigate new methods of self-assembly of guanine-rich DNA sequences into supramolecular structures.
Objective #2 - To develop a hybrid polymer that incorporates transition metal ions into structures created in objective #1 for the transmission of information by electric or magnetic signals..