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

Abstract

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.

Hippocampal-Dependent Cognitive Dysfunction following Repeated Diffuse Rotational Brain Injury in Male and Female Mice

“…Poorer performance on visible platform trials following multiple CHIMERA injuries has been reported in another recent study, which also found impaired performance on a visual cliff task and reduced visual evoked potentials, providing further evidence for behavioral and physiological visual dysfunction. 38 Like many other murine models of CBI, with or without rotational acceleration, 13,[39][40][41][42]46,[70][71][72] pathological analysis of mice following CHIMERA (including the current study) finds significant and often prolonged increased astrogliosis and/or microgliosis in the optic tracts as assessed by GFAP or Iba1 staining, respectively. 14,38,66 Decreased performance on the optokinetic behavioral response test, coupled with decreases in the number of retinal ganglion cells, has also been reported following single or repeated concussive TBI.…”

Long-Term Effects of Repetitive Mild Traumatic Injury on the Visual System in Wild-Type and TDP-43 Transgenic Mice

“…Elevated TDP-43 expression levels in the whole-cell lysates from the injured mouse cortical and hippocampal tissue [ 24 , 25 ], as well as the protein changes in the rat brain following blast TBI [ 26 ], were described. We detected transitory TDP-43 cytoplasmatic translocation and overexpression of the protein and its pathological forms in the frontal cortex within the first week following repetitive mTBI in mice [ 27 ]. Neurodegeneration and gliosis in the optic tracts (OT) of injured wild-type mice and animals with overexpression of human mutant TDP-43 protein (TDP-43 G348C ), a model of ALS/FTLD [ 28 ], were also demonstrated [ 27 ].…”

“…We detected transitory TDP-43 cytoplasmatic translocation and overexpression of the protein and its pathological forms in the frontal cortex within the first week following repetitive mTBI in mice [ 27 ]. Neurodegeneration and gliosis in the optic tracts (OT) of injured wild-type mice and animals with overexpression of human mutant TDP-43 protein (TDP-43 G348C ), a model of ALS/FTLD [ 28 ], were also demonstrated [ 27 ]. In addition, the level of damage in the OT was significantly increased in TDP-43 transgenic animals compared with wild-type mice at the end of the first week after the last injury [ 27 ].…”

“…Neurodegeneration and gliosis in the optic tracts (OT) of injured wild-type mice and animals with overexpression of human mutant TDP-43 protein (TDP-43 G348C ), a model of ALS/FTLD [ 28 ], were also demonstrated [ 27 ]. In addition, the level of damage in the OT was significantly increased in TDP-43 transgenic animals compared with wild-type mice at the end of the first week after the last injury [ 27 ]. TDP-43 G348C mice used in the mentioned study were 9–11 week old animals at the beginning of the study and did not show any neurodegenerative and behavioral impairments before head traumas.…”

“…Such behavior in TDP-43 transgenic mice after repetitive mTBI has not been previously examined. Therefore, considering the results of our previous study and the fact that behavioral and the pathological brain changes are present for months after the initial injuries [ 12 , 27 , 30 , 31 , 32 , 33 ], this research hypothesized that the damage, gliosis, and synaptic reorganization in the OT and the investigated nuclei, as well as behavioral impairments induced by repeated mTBI, would be detected 6 months after the last injury and that they would be more pronounced in TDP-43 G348C mice.…”