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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurol. | doi: 10.3389/fneur.2019.00124

Novel Mouse Tauopathy Model for Repetitive Mild Traumatic Brain Injury: Evaluation of Long-Term Effects on Cognition and Biomarker Levels after Therapeutic Inhibition of Tau Phosphorylation

 Richard Rubenstein1*,  Deep R. Sharma1, Binggong Chang1, Nassima Oumata42, Morgane Cam2, Lise Vaucelle2,  Mattias F. Lindberg2,  Allen Chiu1, Thomas Wisniewski3,  Kevin K. Wang4 and  Laurent Meijer2
  • 1Departments of Neurology and Physiology/Pharmacology, SUNY Downstate Medical Center, United States
  • 2ManRos Therapeutics (France), France
  • 3New York University, United States
  • 4Departments of Emergency Medicine, Psychiatry and Neuroscience, University of Florida, United States

Traumatic brain injury (TBI) is a risk factor for a group of neurodegenerative diseases termed tauopathies, which includes Alzheimer’s disease and chronic traumatic encephalopathy (CTE). Although TBI is stratified by impact severity as either mild (m), moderate or severe, mTBI is the most common and the most difficult to diagnose. Tauopathies are pathologically related by the accumulation of hyperphosphorylated tau (P-tau) and increased total tau (T-tau). Here we describe: (i) a novel human tau-expressing transgenic mouse model, TghTau/PS1, to study repetitive mild closed head injury (rmCHI), (ii) quantitative comparison of T-tau and P-tau from brain and plasma in TghTau/PS1 mice over a 12 month period following rmCHI (and sham), (iii) the usefulness of P-tau as an early- and late-stage blood-based biochemical biomarker for rmCHI, (iii) the influence of kinase-targeted therapeutic intervention on rmCHI-associated cognitive deficits using a combination of lithium chloride (LiCl) and R-roscovitine (ros), and (iv) correlation of behavioral and cognitive changes with concentrations of the brain and blood-based T-tau and P-tau. Compared to sham-treated mice, behavior changes and cognitive deficits of rmCHI-treated TghTau/PS1 mice correlated with increases in both cortex and plasma T-tau and P-tau levels over 12 months. In addition, T-tau, but more predominantly P-tau, levels were significantly reduced in the cortex and plasma by LiCl + ros approaching the biomarker levels in sham and drug-treated sham mice (the drugs had only modest effects on the T-tau and P-tau levels in sham mice) throughout the 12 month study period. Furthermore, although we also observed a reversal of the abnormal behavior and cognitive deficits in the drug-treated rmCHI mice (compared to the untreated rmCHI mice) throughout the time course, these drug-treated effects were most pronounced up until 10 and 12 months where the abnormal behavior and cognition deficits began to gradually increase. These studies describe: (a) a translational relevant animal model for TBI-linked tauopathies, and (b) utilization of T-tau and P-tau as rmCHI biomarkers in plasma to monitor novel therapeutic strategies and treatment regimens for these neurodegenerative diseases.

Keywords: Traumatic Brain Injury, repetitive mild closed head injury, TghTau/PS1 transgenic mice, total tau and phosphorylated tau, Cognition, brain and blood-based biomarkers, roscovitine and lithium chloride

Received: 31 Aug 2018; Accepted: 30 Jan 2019.

Edited by:

Ibolja Cernak, Independent researcher

Reviewed by:

Mark P. Burns, Georgetown University, United States
Bertrand R. Huber, Boston University, United States  

Copyright: © 2019 Rubenstein, Sharma, Chang, Oumata4, Cam, Vaucelle, Lindberg, Chiu, Wisniewski, Wang and Meijer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Richard Rubenstein, SUNY Downstate Medical Center, Departments of Neurology and Physiology/Pharmacology, Brooklyn, 11203, New York, United States, richard.rubenstein@downstate.edu