Radical generation and propagation in biological systems

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Alzheimer's disease (AD) is a devastating neuronal condition of old age that afflicts 10% of the population over the age of 65. It is incurable and results in death usually within 10 years after a painful period of degeneration. It is brought about by the death of nerve cells caused largely by the action of a single small peptide (42-residues), the amyloid beta peptide (Abeta) in aggregated form, most likely with bound, redox active, copper. Abeta's assault on neurons is multipronged. The redox-active copper generates superoxide and hydrogen peroxide, and destroys membranes by initiating lipid peroxidation. The oligomeric form is toxic via a wide variety of mechanisms. For some time we have been applying sophisticated computer modeling to study the fundamental chemistry of the species involved under physiologically relevant conditions. We have examined many aspects of the chemistry of Abeta and its association with the metal, copper. After two years of computer simulation, we have a structure of Abeta itself. We and others believe that the weak link in the complex chain of events leading to neuronal death is the assembly of Abeta into oligomers, and we have expended considerable effort into the design of compounds that will bind specifically to monomeric Abeta. We have designed several families of drug-candidates, and synthesized and tested two of them for their ability to prevent oligomerization and possibly prevent, or at least slow down the progression of, Alzheimer's disease. The present proposal continues our AD chemistry investigation by examining computationally the thermodynamics of peptide-peptide interactions focusing on our drug candidates and targeted segments of Abeta. We also propose to examine the structure of a membrane composed of docosahexaenoic acid, a polyunsaturated fatty acid that is very common in in the brain, its permeability to small species like NO, O2, CO, and H2O2, and its affinity for Abeta. We also propose to study small aggregates of Abeta with bound copper to ascertain their ability to cause restriction of the blood supply to the brain, in order to confirm the hypothesized connection between AD and vascular dementia that we published as the ABSENT hypothesis.