Receptors, Oxidant Stress, and Alzheimer's Disease

Oxygen-free radicals are unstable structures derived from oxygen which can damage cells, affecting their functions in subtle ways and, in some cases, eventuating in cell death. Brain cells or neurons are especially sensitive to oxygen-free radical damage, and other cells important to normal function of the brain, especially those in the blood vessels, undergo a change in their properties which could further promote events leading to poor function of neurons. Cells affected by Alzheimer’s disease show evidence of prolonged and intense contact with oxygen-free radicals. An important mechanism through which such reactive oxygen intermediates form and affect cell function is following the binding of amyloid-beta peptide to a receptor on the cell surface. A receptor is cell surface molecule which allows the cell to specifically bind a target molecule, termed a ligand, thereby resulting in close contact between the cell and ligand, mediated by the receptor. We have isolated a receptor for amyloid-beta peptide, which based on analysis of the sequence of amino acids is, unexpectedly, identical to a receptor we previously studied which has been named RAGE. Based on our pilot data, we hypothesize that the binding of amyloid-beta peptide to neurons, scavenger cells of the brain (microglia), as well as cells in the walls of brain blood vessels, is due to interaction with RAGE. The proposed work is divided into two parts. First, we will identify structures on the amyloid-beta peptide and the receptor which allow the binding to occur in a purified system. Then, using reagents which specifically block access to the receptor, experiments will be performed to determine if this completely prevents interaction of amyloidbeta peptide with the target cells. Second, we will determine if the ability of amyloid-beta peptide to stimulate cells (neurons, microglia and cells of the vessel wall), promoting changes which underlie ultimate degeneration of nerve cells, is due to binding of the peptide to RAGE. If our studies indicate that RAGE is the principal molecule which allows binding of amyloid-beta peptide to target cells, we propose that antagonism of this interaction could represent a future therapeutic possibility for suppressing degeneration of neurons in patients with Alzheimer’s disease.