The effects of mild closed head injuries on tauopathy and cognitive deficits in rodents: Primary results in wild type and rTg4510 mice, and a systematic review.
In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as 'mild' and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping - a novel functional neuroimaging technique - we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established.
['Bachstetter|Adam D|AD|', 'Morganti|Josh M|JM|', 'Bodnar|Colleen N|CN|', 'Webster|Scott J|SJ|', 'Higgins|Emma K|EK|', 'Roberts|Kelly N|KN|', 'Snider|Henry|H|', 'Meier|Shelby E|SE|', 'Nation|Grant K|GK|', 'Goulding|Danielle S|DS|', 'Hamm|Matthew|M|', 'Powell|David K|DK|', 'Vandsburger|Moriel|M|', 'Van Eldik|Linda J|LJ|', 'Abisambra|Jose F|JF|']
D000818:Animals D003072:Cognition Disorders D016489:Head Injuries, Closed D051379:Mice D008818:Mice, Neurologic Mutants D024801:Tauopathies
TBI Tau CTE Concussion Neurodegeneration Rodent behavior