Additionally, we demonstrate that CCI also causes acute Ab accumulation in young APP/PS1 mice, which harbor a different PS1 mutation from 3xTg-AD mice, and acutely accelerates tau pathology in TauP301L transgenic mice. Overall, our CCI model represents a useful tool for LY294002 future investigation into the link between TBI and AD. The current study shows that CCI TBI can cause rapid Ab accumulation in injured axons of young 3xTg-AD mice. This intra-axonal Ab was detectable at 1 hour post injury, and continued to rise monotonically through 24 hours. Several brain regions of injured 3xTg-AD mice also exhibited increased tau immunoreactivity, but the time course was different across regions. In particular, puntate tau staining the ipsilateral fimbria and perinuclear tau staining in the amygdala had a biphasic response with peaks at 1 hour and 24 hours post TBI. Instead, the numbers of tau-positive processes in the contralateral CA1 started to increase at 12 h post injury. However, total tau immunoreactivity in the ipsilateral CA1 of 3xTg-AD mice was not significantly affected by TBI. Neuronal damage to this region may have caused release of tau into the extracellular space, where it could not be detected by immunohistochemistry. Importantly, the finding of post-traumatic Ab accumulation in 3xTg-AD mice was recapitulated in a different transgenic mouse model of Alzheimer’s disease, APP/PS1. Similarly,accelerated tau pathology in 3xTgAD mice was also observed in transgenic mice carrying only TauP301L mutation at 24 hours following TBI. We have previously presented evidence that CCI can independently alter Ab and tau abnormalities in 3xTg-AD mice. Specifically, systemic inhibition of c-secretase activity, an enzyme required for Ab generation from its precursor, APP, successfully blocked post-traumatic Ab accumulation in injured mice. However, tau pathology was unaffected following blockade of Ab generation and accumulation. In the present study, we found distinct anatomical and temporal patterns of Ab and total tau abnormalities throughout 24 hours post TBI in 3xTg-AD mice. Furthermore, we found abnormal total and phospho-tau accumulation in injured axons, and increased somatic tau staining in single-transgenic TauP301L mice subjected to TBI. Although the temporal distribution of phospho-tau following acute TBI in 3xTgAD mice remains to be investigated, findings in this study add additional support to the hypothesis that Ab and tau pathologies are independent in the setting of TBI. As such, future studies will be required to investigate the mechanisms underlying TBIinduced tau hyperphosphorylation. APP, the precursor protein of Ab, has been found to accumulate in injured axons within 30 minutes following central nervous system injury. Axonal APP accumulation has in turn been hypothesized to serve as substrate for intra-axonal Ab generation. Thus, our finding that intra-axonal Ab was detected starting at 1 hour post TBI in 3xTg-AD mice is in line with the reported time for the earliest APP accumulation following brain trauma. PS1 mutations are thought to drive intracellular Ab generation.