Objective: Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration.
Methods: The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler.
Results: The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3β. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p < 0.05), improved cognition (t = 6.532, p < 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p < 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy.
Conclusions: Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.
Keywords: ATF6 = activating transcription factor 6; BiP = binding immunoglobulin protein; CHOP = C/EBP homology protein; CTE = chronic traumatic encephalopathy; DAB = diaminobenzidine; DHA = docosahexaenoic acid; ER = endoplasmic reticulum; GADD34 = growth arrest and DNA damage-inducible protein 34; GSK3β = glycogen synthase kinase-3β; IHC = immunohistochemistry; IRE1α = inositol requiring enzyme 1α; JNK = c-Jun N-terminal kinase; NFL = National Football League; PBS = phosphate-buffered saline; PERK = protein kinase RNA-like ER kinase; PHF = paired helical filament; TBI = traumatic brain injury; WWE = World Wrestling Entertainment; XBP1 = X-box binding protein 1; blast traumatic brain injury; chronic traumatic encephalopathy; docosahexaenoic acid; endoplasmic reticulum stress; hyperphosphorylated tau; p-eIF2a = phosphorylated eukaryotic initiation factor 2α; trauma.