Lipid peroxidation in amyloid plaque formation

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DESCRIPTION (provided by applicant): This is an application for Mentored Research Scientist Development Award (K01) to develop the Principal Investigator's research career in the area of neurodegeneration and oxidative stress. The goal of this award is to provide the Principal Investigator training that will allow him to become an independent investigator in the area of neurodegeneration and oxidative stress with a funded NIH grant by the end of the award. The training program consists of two parts: education/course work/meetings and research. The following is the summary of the research plan. Current research suggests a correlation between oxidative stress, such as lipid peroxidation, and amyloid deposition and plaque formation. However, direct evidence showing the involvement of oxidative stress in the formation of amyloid plaques is lacking. The research in this training program will test the following hypothesis: alterations in lipid peroxidation can affect the deposition of A-beta peptides and alter the levels of amyloid plaques in the brains of mice. Transgenic and knockout mouse models will be used in this study to test the hypothesis. Two mouse models with different PHGPx (phospholipid hydroperoxide glutathione-eroxidase) levels will be used: Gpx4 knockout mice (under-expressing PHGPx) and Gpx4 transgenic mice (over-expressing PHGPx). PHGPx, which is encoded by the Gpx4 gene (glutathione peroxidase gene 4), is a unique anti-oxidant defense enzyme that can detoxify membrane lipid peroxides directly and is considered to be the most important enzyme in removal of lipid hydroperoxides from ceil membranes. These mice will be crossed to APP transgenic mice (Tg2576), which develop amyloid plaques in the brain and show deficits in cognition, to produce APP mice with decreased or increased PHGPx levels. This study consists of four specific aims: (1) To produce transgenic mice that over express PHGPx. (2) To measure the levels of lipid-eroxidation in brains of APP mice with reduced or increased levels of PHGPx. (3) To measure the levels of A-beta'l-42 and A-beta1-40 peptides in brains of APP mice with reduced or increased levels of PHGPx. (4) To measure the levels of amyloid plaques in APP transgenic mice with reduced or increased PHGPx. This study will be the first direct test of the role of lipid peroxidation in amyloid plaque formation.