Traumatic Brain Injury in hTau Model Mice: Enhanced Acute Macrophage Response and Altered Long-Term Recovery

Olga N. Kokiko-Cochran, Maha Saber, Shweta Puntambekar, Shane M. Bemiller, Atsuko Katsumoto, Yu Shang Lee, Kiran Bhaskar, Richard M. Ransohoff, Bruce T. Lamb

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6 Scopus citations

Abstract

Traumatic brain injury (TBI) induces widespread neuroinflammation and accumulation of microtubule associated protein tau (MAPT): two key pathological features of tauopathies. This study sought to characterize the microglial/macrophage response to TBI in genomic-based MAPT transgenic mice in a Mapt knockout background (called hTau). Two-month-old hTau and age-matched control male and female mice received a single lateral fluid percussion TBI or sham injury. Separate groups of mice were aged to an acute (3 days post-injury [DPI]) or chronic (135 DPI) post-injury time point. As judged by tissue immunostaining for macrophage markers, microglial/macrophage response to TBI was enhanced at 3 DPI in hTau mice compared with control TBI and sham mice. However, MAPT phosphorylation increased in hTau mice regardless of injury group. Flow cytometric analysis revealed distinct populations of microglia and macrophages within all groups at 135 DPI. Unexpectedly, microglial reactivity was significantly reduced in hTau TBI mice compared with all other groups. Instead, hTau TBI mice showed a persistent macrophage response. In addition, TBI enhanced MAPT pathology in the temporal cortex and hippocampus of hTau TBI mice compared with controls 135 DPI. A battery of behavioral tests revealed that TBI in hTau mice resulted in compromised use of spatial search strategies to complete a water maze task, despite lack of motor or visual deficits. Collectively, these data indicate that the presence of wild-type human tau alters the microglial/macrophage response to a single TBI, induces delayed, region-specific MAPT pathology, and alters cognitive recovery; however, the causal relationship between these events remains unclear. These results highlight the potential significance of communication between MAPT and microglia/macrophages following TBI, and emphasize the role of neuroinflammation in post-injury recovery.

Original languageEnglish (US)
Pages (from-to)73-84
Number of pages12
JournalJournal of neurotrauma
Volume35
Issue number1
DOIs
StatePublished - Jan 1 2018

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Keywords

  • MAPT
  • TBI
  • neuroinflammation
  • spatial memory

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Kokiko-Cochran, O. N., Saber, M., Puntambekar, S., Bemiller, S. M., Katsumoto, A., Lee, Y. S., Bhaskar, K., Ransohoff, R. M., & Lamb, B. T. (2018). Traumatic Brain Injury in hTau Model Mice: Enhanced Acute Macrophage Response and Altered Long-Term Recovery. Journal of neurotrauma, 35(1), 73-84. https://doi.org/10.1089/neu.2017.5203