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Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans

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Abstract

The pathologic phosphorylation and sub-cellular translocation of neuronal transactive response-DNA binding protein (TDP-43) was identified as the major disease protein in frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions, now termed FTLD-TDP, and amyotrophic lateral sclerosis (ALS). More recently, TDP-43 proteinopathy has been reported in dementia pugilistica or chronic traumatic encephalopathy caused by repetitive traumatic brain injury (TBI). While a single TBI has been linked to the development of Alzheimer’s disease and an increased frequency of neurofibrillary tangles, TDP-43 proteinopathy has not been examined with survival following a single TBI. Using immunohistochemistry specific for both pathological phosphorylated TDP-43 (p-TDP-43) and phosphorylation-independent TDP-43 (pi-TDP-43), we examined acute (n = 23: Survival < 2 weeks) and long-term (n = 39; 1–47 years survival) survivors of a single TBI versus age-matched controls (n = 47). Multiple regions were examined including the hippocampus, medial temporal lobe, cingulate gyrus, superior frontal gyrus and brainstem. No association was found between a history of single TBI and abnormally phosphorylated TDP-43 (p-TDP-43) inclusions. Specifically, just 3 of 62 TBI cases displayed p-TDP-43 pathology versus 2 of 47 control cases. However, while aggregates of p-TDP-43 were not increased acutely or long-term following TBI, immunoreactivity to phosphorylation-independent TDP-43 was commonly increased in the cytoplasm following TBI with both acute and long-term survival. Moreover, while single TBI can induce multiple long-term neurodegenerative changes, the absence of TDP-43 proteinopathy may indicate a fundamental difference in the processes induced following single TBI from those of repetitive TBI.

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Acknowledgments

This work was supported by National Institutes of Health grants NS038104, AG10124, AG17546 and NS056202. We would also like to thank Ms. Janice E. Stewart for her technical assistance with immunohistochemical staining procedures.

Conflict of interest

None of the authors have any conflict of Interest to declare.

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Authors and Affiliations

  1. Department of Neurosurgery, Penn Center for Brain Injury and Repair, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA, 19104, USA

    Victoria E. Johnson & Douglas H. Smith

  2. Division of Clinical Neurosciences, University of Glasgow, Glasgow, UK

    Victoria E. Johnson & William Stewart

  3. Department of Neuropathology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK

    William Stewart

  4. Department Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    John Q. Trojanowski

  5. Alzheimer’s Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    John Q. Trojanowski

  6. Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    John Q. Trojanowski

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  1. Victoria E. Johnson
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  2. William Stewart
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  3. John Q. Trojanowski
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  4. Douglas H. Smith
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Correspondence to Douglas H. Smith.

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Johnson, V.E., Stewart, W., Trojanowski, J.Q. et al. Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans. Acta Neuropathol 122, 715–726 (2011). https://doi.org/10.1007/s00401-011-0909-9

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