Apolipoprotein E genotype and oxidative stress response to traumatic brain injury.
Traumatic Brain Injury (TBI) is known to result in oxidative stress, and as variation at the Apolipoprotein E (APOE) gene has been shown to influence outcome following TBI, but through as yet unclear mechanisms, we used transgenic APOE mouse models to examine the relationship between APOE genotype and oxidative stress following TBI. We administered a controlled cortical impact (CCI) injury or sham injury to transgenic mice expressing either human APOE3 or APOE4 on a murine APOE-deficient background. RNA was prepared from the ipsilateral hippocampi and cortices retrieved at 24 h and 1 month post-TBI. Microarray analysis was performed on unpooled samples from three mice per group to determine the genomic 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 ApoE3 compared to ApoE4. However, in an additional cohort of mice we isolated the ipsilateral hippocampi, cortices, and cerebella at 1 month after TBI or sham injury 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 of injury 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 dependent effects on outcome following TBI.
Ferguson
S
S
The Roskamp Institute, 2040 Whitfield Avenue, 34243, Sarasota, FL, USA. sferguson@rfdn.org
Mouzon
B
B
Kayihan
G
G
Wood
M
M
Poon
F
F
Doore
S
S
Mathura
V
V
Humphrey
J
J
O'Steen
B
B
Hayes
R
R
Roses
A
A
Mullan
M
M
Crawford
F
F
D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D001930:Brain Injuries / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D018384:Oxidative Stress
D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E