Blast Exposure Causes Early and Persistent Aberrant Phospho- and Cleaved-Tau Expression in a Murine Model of Mild Blast-Induced Traumatic Brain Injury

Abstract

Mild traumatic brain injury (mTBI) is considered the ‘signature injury’ of combat veterans that have served during the wars in Iraq and Afghanistan. This prevalence of mTBI is due in part to the common exposure to high explosive blasts in combat zones. In addition to the threats of blunt impact trauma caused by flying objects and the head itself being propelled against objects, the primary blast overpressure (BOP) generated by high explosives is capable of injuring the brain. Compared to other means of causing TBI, the pathophysiology of mild-to-moderate BOP is less well understood. To study the consequences of BOP exposure in mice, we employed a well-established approach using a compressed gas-driven shock tube that recapitulates battlefield-relevant open-field BOP. We found that 24 hours post-blast a single mild BOP provoked elevation of multiple phosphor- and cleaved-tau species in neurons, as well as elevating manganese superoxide-dismutase (MnSOD or SOD2) levels, a cellular response to oxidative stress. In hippocampus, aberrant tau species persisted for at least 30 days post-exposure, while SOD2 levels returned to sham control levels. These findings suggest that elevated phospho- and cleaved-tau species may be among the initiating pathologic processes induced by mild blast exposure. These findings may have important implications for efforts to prevent blast-induced insults to the brain from progressing into long-term neurodegenerative disease processes.

Tau Oligomers Derived from Traumatic Brain Injury Cause Cognitive Impairment and Accelerate Onset of Pathology in Htau Mice

“…40 Blast injury in humans and experimental animals is associated with increased levels of total and phosphorylated tau protein. 18,[40][41][42] We have previously shown that an increase in levels of tau oligomers results from fluid percussion TBI rats. 21 However, the contribution of tau oligomers to blast TBI has not yet been investigated.…”

“…[12][13][14] There have been many hypotheses about the causes of this ongoing injury, 14,15 including involvement of tau pathology. [16][17][18][19][20] Recently, we proposed a possible mechanism, based on accumulation and spreading of a toxic form of tau protein, known as tau oligomers. 21 A large body of research has suggested recently that toxicity of tau protein in neurodegenerative disorders, such as Alzheimer's disease (AD), does not depend on the fibrillar aggregates, neurofibrillary tangles, long known to be hallmarks of the disease.…”

Neuronal DNA Methylation Profiling of Blast-Related Traumatic Brain Injury

“…10,11,14,21,22 However, even low-level blast pressure waves are transmitted to the brain and exert a variety of biochemical, pathological, and physiological effects in animals, including the induction of chronic behavioral effects. 3,10,14,[21][22][23][24][25][26][27][28][29] Modulation of gene expression mediated by epigenetic changes, such as deoxyribonucleic acid (DNA) methylation, is one way the brain creates new homeostasis in response to experience, including response to injury. 30 Aberrant regulation of gene expression contributes to long-lasting behavioral abnormalities, where epigenetic modifications serve as a regulatory layer decoding environmental signals into sustained changes in gene expression.…”

On the prospective contributions of the shock physics community to outstanding issues concerning blast-induced traumatic brain injury

“…However, it is unfortunately not standard practice. While few researchers have purposely designed experiments to generate scaled-down exposure conditions [14,32,33] against small mammals, others expose animal models to blast parameters relevant to humans [27,[34][35][36][37][38][39][40][41][42][43]. Assuming mass scaling is relevant to bTBI, some of these exposures may effectively result in exposing an animal model to nuclear-sized blasts [29].…”