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2006 Grant - Sayre
Lipid Oxidation in Alzheimer's Disease: Mechanisms of Toxicity and Potential Intervention
Lawrence M. Sayre, Ph.D.
Case Western Reserve University
2006 Investigator-Initiated Research Grant
Research shows that the brains of people with Alzheimer's disease are exposed to oxidative stress, a term used to describe chemical reactions between oxygen and other molecules that make up the cells and tissues of the human body. Such oxidation reactions can damage essential cellular compon-ents, such as DNA and protein, and can cause otherwise healthy cells to die.
One of the products of oxidative stress is a chemical called 4-hydroxy-2-nonenal (HNE). This is formed when oxygen reacts with polyunsaturated fatty acids. HNE can go on to react with and deactivate proteins and DNA. In fact, HNE has been found bound to protein aggregates in the brain called amyloid plaques and neurofibrillary tangles, which are hallmarks of Alzheimer's disease.
Lawrence Sayre, Ph.D., and colleagues plan to study the role of HNE, and another more reactive molecule called ONE, in Alzheimer's disease. He has proposed to develop sensitive methods for detecting proteins that have reacted with these and similar chemicals called aldehydes. The purpose of this strategy is to determine the relative amounts of each of the toxic compounds in the brain. He will also determine which of these chemicals is more toxic to neurons and which is more likely to react with tau, the major component of neurofibrillary tangles.
This work will lead to a much better understanding of the role of oxidative stress in Alzheimer's disease and could spur the development of novel therapeutics. Dr. Sayre's team will evaluate the potential of drugs called aldehyde traps to protect neurons from oxidative stress.