Abstract
Chronic neurodegeneration following a history of neurotrauma is frequently associated with neuropsychiatric and cognitive symptoms. In order to enhance understanding about the underlying pathophysiology linking neurotrauma to neurodegeneration, a multi-model preclinical approach must be established to account for the different injury paradigms and pathophysiologic mechanisms. We investigated the development of tau pathology and behavioral changes using a multi-model and multi-institutional approach, comparing the preclinical results to tauopathy patterns seen in post-mortem human samples from athletes diagnosed with chronic traumatic encephalopathy (CTE). We utilized a scaled and validated blast-induced traumatic brain injury model in rats and a modified pneumatic closed-head impact model in mice. Tau hyperphosphorylation was evaluated by western blot and immunohistochemistry. Elevated-plus maze and Morris water maze were employed to measure impulsive-like behavior and cognitive deficits respectively. Animals exposed to single blast (~50 PSI reflected peak overpressure) exhibited elevated AT8 immunoreactivity in the contralateral hippocampus at 1 month compared to controls (q = 3.96, p < 0.05). Animals exposed to repeat blast (six blasts over 2 weeks) had increased AT8 (q = 8.12, p < 0.001) and AT270 (q = 4.03, p < 0.05) in the contralateral hippocampus at 1 month post-injury compared to controls. In the modified controlled closed-head impact mouse model, no significant difference in AT8 was seen at 7 days, however a significant elevation was detected at 1 month following injury in the ipsilateral hippocampus compared to control (q = 4.34, p < 0.05). Elevated-plus maze data revealed that rats exposed to single blast (q = 3.53, p < 0.05) and repeat blast (q = 4.21, p < 0.05) spent more time in seconds exploring the open arms compared to controls. Morris water maze testing revealed a significant difference between groups in acquisition times on days 22–27. During the probe trial, single blast (t = 6.44, p < 0.05) and repeat blast (t = 8.00, p < 0.05) rats spent less time in seconds exploring where the platform had been located compared to controls. This study provides a multi-model example of replicating tau and behavioral changes in animals and provides a foundation for future investigation of CTE disease pathophysiology and therapeutic development.
Highlights
Current limitations in understanding chronic traumatic encephalopathy (CTE) pathophysiology are unlikely to be addressed in a clinical population in the near future due to the challenges associated with establishing long-term, prospective cohort studies in such a population
The quest for elucidating CTE pathophysiology development is ongoing with the goal of targeting specific injurious cascades a key priority in order to prevent the emergence of clinical symptoms
While the clinical literature has been inundated with reports of CTE in athletes and soldiers alike, few experimental tools exist for investigating disease pathophysiology, establishing diagnostic criteria, and discovering preventative or therapeutic agents
Summary
Current limitations in understanding CTE pathophysiology are unlikely to be addressed in a clinical population in the near future due to the challenges associated with establishing long-term, prospective cohort studies in such a population. Few preclinical models of CTE have been proposed that sufficiently demonstrate both the requisite tauopathy and behavioral changes attributed to CTE [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. The purpose of this paper is to present two preclinical models that successfully reproduce some neuropathological and behavioral changes consistent with CTE-like phenotypes, and discuss future directions for CTE animal modeling. The quest for elucidating CTE pathophysiology development is ongoing with the goal of targeting specific injurious cascades a key priority in order to prevent the emergence of clinical symptoms
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