Lack of effect of repetitive mild traumatic brain injury early in life on the neuropathological and behavioral hallmarks of Alzheimer's disease in 3xTg-AD mice

Background: Repetitive traumatic brain injuries (rTBIs) are predicted to increase risk for neurodegenerative disorders including Alzheimer's disease (AD). Objective: By using a combination of behavioral tests and histopathology, we investigated whether brain trauma worsens cognitive dysfunction and brain pathology in 3xTg-AD mice subjected early in life to repetitive mild TBI (rmTBI). Methods: At 3 months old, mice in the rmTBI group were given 5 mTBIs, each separated by 48 h. Mice were aged to 10 months old and assessed for cognitive function using the Barnes maze and Novel Object Recognition behavioral tests. Hippocampal sections were stained for amyloid-β and phosphorylated-tau proteins that constitute pathological hallmarks of AD. Immunostaining for GFAP and Iba1 was also employed to assess glial reactivity in the hippocampus. Results: Results from the behavioral tests indicate that there are no significant differences in the severity of cognitive dysfunction between any of the 3xTg-AD mouse groups (naïve, SHAM, or rmTBI). As expected, wild-type mice perform better across all behavioral tests than any of the 3xTg-AD mice. Furthermore, we do not find any significant difference in the amount of amyloid-β aggregation, tau phosphorylation, or gliosis between rmTBI and control (naïve or SHAM) 3xTg-AD mouse groups. Conclusions: Collectively, our data show that rmTBIs early in life do not accelerate progression or enhance the magnitude of disease in mice that are genetically predisposed to developing AD. These findings suggest that the young brain is quite resilient to trauma and that an enhanced risk of neurodegeneration is not an inescapable conclusion of a history of rmTBI.