Linking Traumatic Brain Injury to Chronic Traumatic Encephalopathy: Identification of Potential Mechanisms Leading to Neurofibrillary Tangle Development

Abstract

Significant attention has recently been drawn to the potential link between head trauma and the development of neurodegenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sportsrelated concussions in athletes and blast-induced traumatic brain injury in soldiers elevates the risk for future development of chronic neurodegenerative diseases such as CTE. CTE is a progressive disease distinguished by characteristic tau neurofibrillary tangles (NFTs) and, occasionally, transactive response DNA binding protein 43 (TDP43) oligomers, both of which have a predilection for perivascular and subcortical areas near reactive astrocytes and microglia. The disease is currently only diagnosed postmortem by neuropathological identification of NFTs. A recent workshop sponsored by National Institute of Neurological Disorders and Stroke emphasized the need for premortem diagnosis, to better understand disease pathophysiology and to develop targeted treatments. In order to accomplish this objective, it is necessary to discover the mechanistic link between acute neurotrauma and the development of chronic neurodegenerative and neuropsychiatric disorders such as CTE. In this review, we briefly summarize what is currently known about CTE development and pathophysiology, and subsequently discuss injury-induced pathways that warrant further investigation. Understanding the mechanistic link between acute brain injury and chronic neurodegeneration will facilitate the development of appropriate diagnostic and therapeutic options for CTE and other related disorders.

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

“…24 The ER stress response consists of three arms: protein kinase RNA-like ER kinase (PERK), inositol requiring enzyme 1a (IRE1a), and activating transcription factor 6 (ATF6). The arms are activated when binding immunoglobulin protein (BiP) dissociates from the ER membrane, signaling an increase in unfolded proteins.…”

Temporal Lobe Epilepsy, Stroke, and Traumatic Brain Injury: Mechanisms of Hyperpolarized, Depolarized, and Flow-Through Ion Channels Utilized as Tri-Coordinate Biomarkers of Electrophysiologic Dysfunction

“…The hyperpolarization as opposed to depolarization gating make the HCN1 channel an excellent candidate for integrated research with NKCC1 and KCC2 co-transporter channels along with the depolarization gating of the high voltage-gated CaV channels. The construction of the HCN1 channel pore has great conservation with that of the K + channels; both contain the glycine-tyrosine-glycine (GYG) as a selectivity filter [38]. The function of the HCN1 channel is to operate with reverse polarity and it does this by structural design that allows for conformational changes of the pore based on the trigger mechanism.…”

Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

“…It is likely that the hyperphosphorylation will only occur in the context of tau acetylation. A shift in favor of the tau kinases over the phosphatases most likely occurs [37]. In Irwin's seminal paper, there is co-localization of acetylated K280 with multiple p-tau epitopes in post-mortem AD brains [38].…”