Evidence for accelerated tauopathy in the retina of transgenic P301S tau mice exposed to repetitive mild traumatic brain injury
Xu L, Ryu J, Nguyen JV, Arena J, Rha E, Vranis P, Hitt D, Marsh-Armstrong N, Koliatsos VE. Exp Neurol. 2015; ahead of print.
Take Home Message: Single and repetitive mild traumatic brain injury (mTBI) accelerates tauopathy among mice genetically predisposed to tau build up.
In recent years, we’ve heard about the possible relationship between repetitive mild traumatic brain injury (mTBI) within contact and collision sports and chronic traumatic encephalopathy (CTE) - an aggregation of the protein tau in tangles or tauopathy. However, not all exposed athletes develop this condition. Thus, genetic factors may play a role in the risk of developing CTE because genes code for proteins (for example, tau protein) that respond to mechanical stress. Therefore, the authors tested whether mice, who were prone to tauopathy because of changes in the tau gene, would experience accelerated onset of tauopathy after mTBI. The authors used 5-week old (adolescent to young adult age) mice. These mice were exposed to different mTBI regimens: single head impact, 4 head impacts (4 impacts on 4 separate days), 12 head impacts (3 repetitive impacts on 4 different days), or no head impacts (control). Four mice were included in each group. The authors measured neurological function using the neurological severity score, which uses a 10-point scale system to assess neurobehavioral outcomes in rodents after a brain injury. Once the mouse completed his/her head impact protocol the authors dissected and preserved brain tissues to observe differences between groups. Among mice susceptible to tauopathy, the density of tau in a vulnerable region increased 20 fold with one mTBI hit, over 50 fold with 4 mTBI hits, and 60 fold with 12 mTBI hits compared with susceptible mice without an mTBI. There was very little tau observed in the vulnerable region in sham mice compared with those in the injured groups. There were no differences in tau build up in the cerebral cortex (a region not commonly affected with tauopathy) between the 4-impact and 12-impact regimen groups. The number of hits was a factor related to tauopathy. The authors had previously demonstrated that mice, who are not genetically predisposed to tauopathy, lack evidence of tauopathy after mTBI.
The authors found that among mice susceptible to tauopathy a single mTBI event may have an effect on the progression of tauopathy, but repetitive injury has an even greater effect. The absence of an excessive buildup of tau in cortex between sham and mTBI groups may suggest that the accelerated tauopathy after repetitive mTBI is not a generic property of the susceptible brain. Instead it may be tied to brain regions undergoing more stress. The authors demonstrated that mice genetically prone to tau buildup develop higher amounts of tau, especially with more head impacts. Determining genetic risk factors could help develop therapeutic agents to alter tau buildup and help us council athletes who are genetically susceptible for diseases associated with repetitive head impacts such as CTE. At this time, medical professionals need to be aware of the risks of repetitive head impacts, and educate their athletes about the risks like CTE. This study is a nice reminder that not everyone will get CTE but it is critical that we discover why some patients do.
Questions for Discussion: When you educate athletes about concussion, do you mention long-term problems like CTE? Do you think athletes would be more likely to report head impacts if they knew it could lead to a long-term disease like CTE?
Written by: Jane McDevitt, PhD
Reviewed by: Jeff Driban