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

Adam D. Bachstetter, Josh M. Morganti, Colleen N. Bodnar, Scott J. Webster, Emma K. Higgins, Kelly N. Roberts, Henry Snider, Shelby E. Meier, Grant K. Nation, Danielle S. Goulding, Matthew Hamm, David K. Powell, Moriel Vandsburger, Linda J. Van Eldik, Jose F. Abisambra

Research output: Contribution to journalReview articlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish
Article number113180
JournalExperimental Neurology
Volume326
DOIs
StatePublished - Apr 2020

Bibliographical note

Publisher Copyright:
© 2020

Keywords

  • CTE
  • Concussion
  • Neurodegeneration
  • Rodent behavior
  • TBI
  • Tau

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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