APOLIPOPROTEIN E GENOTYPE AND OXIDATIVE STRESS RESPONSE TO TRAUMATIC BRAIN INJURY

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By S. FERGUSON,a* B. MOUZON,a G. KAYIHAN, a M. WOOD, a F. POON, a S. DOORE, a V. MATHURA, a

J. HUMPHREY, a B. O’STEEN, b R. HAYES, c A. ROSES, d M. MULLANa AND F. CRAWFORDa

aThe Roskamp Institute, 2040 Whitfield Avenue, 34243, Sarasota, FL,

USA

bCenter for Traumatic Brain Injury Studies, McKnight Brain Institute of

the University of Florida, 100 Newell Drive, Gainesville, FL, USA

cBanyan Biomarkers, 12085 Research Drive, 32615, Alachua, FL,

USA dR. David Thomas Executive Training Center, Duke University, One

Science Drive, Suite 342, Durham, NC, USA

Abstract—Traumatic Brain Injury (TBI) is known to result in oxidative stress, which is an increase or imbalance in the amount of cytotoxic oxidants and free radicals beyond what the cell can normally handle.  The Apolipoprotein E (APOE) gene has different variations called alleles, with two of the most common known as APOE3 and APOE4.  The different APOE alleles have been shown to influence outcome following TBI in different ways, with the APOE4 allele being associated with poor outcome, but through as yet unclear mechanisms, so we used transgenic APOE mouse models to examine the relationship between APOE genotype and oxidative stress following TBI.  Mice transgenic for either human APOE3 or APOE4 on a murine APOE-deficient background were examined in an approved model of TBI. RNA was prepared from the ipsilateral hippocampi and cortices retrieved at 24 h and 1 month post-TBI. Microarray (“gene chip”) analysis was performed on individual samples from three mice per group to determine the way different genes are turned on or off in response to TBI and to specifically investigate the response of genes involved in oxidative stress mechanisms. Our data demonstrated TBI-induced expression of many more anti-oxidant related genes in the APOE3 mice, suggesting a potential anti-oxidative role for the ApoE3 compared to ApoE4. However, in an additional cohort of mice we isolated the ipsilateral hippocampi, cortices, and cerebella at 1 month after TBI for immunohistochemical analysis of markers of oxidative stress: the formation and presence of carbonyls (indication of general oxidative modification), 3-nitrotyrosine (3NT; specific to protein modification), or 4-hydroxyl-2-nonenal (HNE; specific to lipid peroxidation). Although we observed significant increases in all three markers of oxidative stress in response to injury, and genotype was a significant factor for carbonyl and 3NT, we found no significant interaction between genotype and injury. This may be due to the overwhelming effect  injury has on the oxidative stress level compared to genotype in our ANOVA, but nonetheless suggests that an influence on oxidative stress response is not the primary mechanism behind the APOE-genotype specific differences of outcome following TBI.

To reach the article that was published in Neuroscience Volume 168, Issue 3, 14 July 2010, Pages 811-819, please follow the link.

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