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

Article type: Research Article

Authors: Huber, Bertrand R.^{a; 1} | Meabon, James S.^{b; c; 1} | Martin, Tobin J.^c | Mourad, Pierre D.^{d; e; f} | Bennett, Raymond^g | Kraemer, Brian C.^{c; h} | Cernak, Iboljaⁱ | Petrie, Eric C.^{a; b} | Emery, Michael J.^j | Swenson, Erik R.^{j; k} | Mayer, Cynthia^a | Mehic, Edin^f | Peskind, Elaine R.^{a; b} | Cook, David G.^{c; h; l; *}

Affiliations: [a] Northwest Network Mental Illness, Research, Education, and Clinical Center (MIRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA | [b] Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA | [c] Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA | [d] Department of Neurological Surgery, University of Washington, Seattle, WA, USA | [e] Applied Physics Laboratory, University of Washington, Seattle, WA, USA | [f] Department of Bioengineering, University of Washington, Seattle, WA, USA | [g] Baker Engineering and Risk Consultants, San Antonio, TX, USA | [h] Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA | [i] Canadian Military and Veterans' Clinical Rehabilitation, Faculty of Rehabilitation Medicine, University of Alberta, AB, Canada | [j] Pulmonary and Critical Care Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA | [k] Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA | [l] Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA

Correspondence: [*] Correspondence to: David G. Cook, PhD, 1660 S. Columbian Way, Seattle, WA 98108, USA. Tel.: +1 206 768 5437; E-mail: [email protected].

Note: [1] These authors contributed equally to this manuscript.

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 phospho- 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.

Keywords: Blast-induced neurotrauma, brain trauma, cerebellum, mitochondrial oxidative stress, neurodegeneration, tauopathy

DOI: 10.3233/JAD-130182

Journal: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 309-323, 2013