Repetitive Traumatic Brain Injury Is Associated With TDP-43 Alterations, Neurodegeneration, and Glial Activation in Mice

J Neuropathol Exp Neurol. 2021 Jan 1;80(1):2-14. doi: 10.1093/jnen/nlaa130.


Increasing evidence points to a relationship between repetitive mild traumatic brain injury (mTBI), the Tar DNA binding protein 43 (TDP-43) pathology and some neurodegenerative diseases, but the underlying pathophysiological mechanisms are still unknown. We examined TDP-43 regulation, neurodegeneration, and glial responses following repetitive mTBI in nontransgenic mice and in animals with overexpression of human mutant TDP-43 protein (TDP-43G348C). In the frontal cortices of the injured nontransgenic animals, early TDP-43 cytoplasmatic translocation and overexpression of the protein and its pathological forms were detected. In the injured animals of both genotypes, neurodegeneration and pronounced glial activity were detected in the optic tract. In TDP-43G348C mice, these changes were significantly higher at day 7 after the last mTBI compared with the values in the nontransgenic animals. Results of this study suggest that the changes in the TDP-43 regulation in the frontal cortices of the nontransgenic animals were a transient stress response to the brain injury. Repetitive mTBI did not produce additional TDP-43 dysregulation or neurodegeneration or pronounced gliosis in the frontal cortex of TDP-43G348C mice. Our research also suggests that overexpression of mutated human TDP-43 possibly predisposes the brain to more intense neurodegeneration and glial activation in the optic tract after repetitive mTBI.

Keywords: Brain concussion; Mouse; Nerve degeneration; Neuroglia; TDP-43 protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Concussion / metabolism
  • Brain Concussion / pathology
  • Brain Injuries, Traumatic / metabolism*
  • Brain Injuries, Traumatic / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Frontal Lobe / metabolism*
  • Frontal Lobe / pathology
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Neuroglia / metabolism*
  • Neuroglia / pathology


  • DNA-Binding Proteins
  • TDP-43 protein, mouse