The effect of repeat mild traumatic brain injury in the adolescent rat on Alzheimer's disease pathogenesis

Repeat mild traumatic brain injury (RTBI) is highly prevalent among adolescents in the form of recurrent sport concussions. This epidemic is of particular concern due to its potential correlation with neurodegenerative disease. Moderate to severe TBI is a known risk factor for Alzheimer’s disease (AD), but a clear relationship between RTBI and AD has not yet been established. Moreover, two critical questions are 1) does the interval between repeat injuries alter the outcome measure, and 2) are there gender differences?Since wild-type rats do not generate ample Aβ, triple transgenic Alzheimer’s rats (3xTg-AD) were required for the Aβ-related experiments. To determine a correlation between RTBI in adolescence and accelerated Aβ pathogenesis, as well as to establish the effect of a varied brain impact interval (BII), postnatal day 35 3xTg-AD rats received a sham injury, four injuries spaced 24 hours apart (4RTBI24), or four injuries spaced 72 hours apart (4RTBI72). Aβ burden was analyzed in the hippocampus, entorhinal cortex, and parietal cortex 10.5 months after the last injury, demonstrating an increased burden in the hippocampus after 4RTBI24. Interestingly, when BII extended to 72 hours, Aβ burden was not significantly different from sham. These findings were not different between males and females.Two potential mechanistic links between RTBI and accelerated Aβ pathology were assessed in Chapter 2 and Chapter 3. First, traumatic axonal injury (TAI) was measured using diffusion tensor imaging (DTI) and analyzed using tract-based spatial statistics (TBSS). Fractional anisotropy decreased 1 week after 4RTBI24 in the corpus callosum and external capsule, but returned to baseline by 6 months. Second, biochemical analysis demonstrated an increase in Aβ oligomers, despite any changes in BACE1 or PS1, the cleavage enzymes required to produce the Aβ peptide. This dissertation demonstrates a potential correlation between RTBI in adolescence and accelerated AD pathology, which might be eliminated if the BII is increased to allow for metabolic recovery between injuries