APOE Genotype Specific Effects on the Early Neurodegenerative Sequelae Following Chronic Repeated Mild Traumatic Brain Injury

Abstract Repeated mild traumatic brain injury (r-mTBI) can potentially manifest into chronic traumatic encephalopathy (CTE). The apolipoprotein E (APOE4) genotype, a well-recognized potent genetic risk factor in age-related neurodegenerative diseases such as Alzheimer's disease, has been linked to worse outcome after TBI in individuals who carry this allele. The underlying molecular modifications triggered by APOE genotype following r-mTBI remain elusive. We addressed the influence of APOE genotype on TBI dependent tau pathology in middle-aged mice. Using a previously established experimental mTBI protocol in a new repetitive injury paradigm, we report the pathological changes that occurred following one-month of repetitive injuries in APOE3/4 gene targeted mice. Firstly, pathological assessment demonstrated evidence of microgliosis and astrogliosis in the corpus callosum of injured animals, but there was no APOE dependent genotype effect on injury. However, in the parietal cortex Iba1-immunoreactivity was significantly increased in injured versus sham APOE3 mice, but not in APOE4 mice. No effects were observed in soluble amyloid levels with injury or interaction with genotype. APOE4 mice showed significant increases in the tau conformational marker MC1, neurofilament H, brain phospholipids, and endothelial specific oxidized low density lipoprotein receptor in cortical homogenates obtained from injured mice compared to sham counterparts. This pilot work suggests APOE3 and APOE4 specific effects following injury in a mouse model of r-mTBI. These changes may underlie the molecular changes that trigger the vulnerability and increased risk of developing neurodegenerative diseases in aged individuals exposed to repetitive mTBI.