Linking Traumatic Brain Injury to Chronic Traumatic
Encephalopathy: Identification of Potential Mechanisms
Leading to Neurofibrillary Tangle Development
Brandon Peter Lucke-Wold,1,2Ryan Coddington Turner,1,2Aric Flint Logsdon,2,3
Julian Edwin Bailes,4Jason Delwyn Huber,2,3and Charles Lee Rosen1,2
Significant attention has recently been drawn to the potential link between head trauma and the development of neuro-
degenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sports-
related 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 under-
stand 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 neu-
ropsychiatric disorders such as CTE. In this review, we briefly summarize what is currently known about CTE devel-
opment 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 devel-
opment of appropriate diagnostic and therapeutic options for CTE and other related disorders.
Key words: chronic traumatic encephalopathy; neurofibrillary tangles
States alone, >1,700,000 traumatic brain injuries (TBIs) occur.2
Many of these TBIs are related to participation in contact sports,
such as football andhockey, but ahigh rate ofneurotrauma has also
fact, the United States Department of Defense labeled blast-in-
duced TBI (bTBI) as the ‘‘signature injury’’ of the recent wars in
Iraq and Afghanistan.1The estimated annual cost of treatment for
bTBI in the United States is 2.5 billion dollars.4The enormous
of cognitive, motor, and psychiatric problems in blast-exposed
veterans and civilians.5These clinical symptoms, emerging in
former athletes and soldiers alike, are often the first measurable
signs for the development of a chronic neurodegenerative disease
eurotrauma is one of the most common injuries in con-
tact sports and military conflicts.1Each year in the United
such as chronic traumatic encephalopathy (CTE).3Clinical pre-
sentation of CTE has recently been divided into two categories:
young age of onset with primarily psychiatric and behavioral
problems, and older age of onset with primarily cognitive and
motor deficits.6Increased awareness about CTE has prompted
widespread investigation into the progression and pathophysiology
of this disease.7
The two populations at greatest risk for development of CTE are
professional athletes and soldiers.5It appears that individuals with
one or two copies of the apolipoprotein e4 (APOe4) allele have
poorer outcome following head trauma and are at increased risk
for developing CTE following TBI.8Athletes exposed to sub-
concussive and concussive injury, as well as soldiers exposed
to even a single blast, can develop behavioral and psychiatric
problems within a single year following injury.9An area in need
of further investigation is how acute neurotrauma relates to
and/or causes chronic neurodegenerative diseases in susceptible
1Department of Neurosurgery,2The Center for Neuroscience, and3Department of Basic Pharmaceutical Sciences, West Virginia University School of
Medicine, Morgantown, West Virginia.
4Department of Neurosurgery, NorthShore University Health System, University of Chicago Pritzker School of Medicine, Evanston, Illinois.
JOURNAL OF NEUROTRAUMA 31:1129–1138 (July 1, 2014)
ª Mary Ann Liebert, Inc.
individuals. In this review, we examine tau-based CTE patho-
physiology and disease progression while discussing potential
mechanistic pathways that may link acute neurotrauma with
tangle (NFT) formation.
Neuropathological Findings in CTE
Postmortem examination is currently the only widely utilized
and accepted method by which CTE is diagnosed clinically, al-
though in vivo approaches have been identified and are currently
under development for diagnosis and tracking premortem.3,10
Common neuropathological findings of CTE include NFTs and
transactive response DNA binding protein 43 (TDP43), as well as
microglial and astrocyte activation.11Although the mechanistic
the current understanding of the pathological progression will be
discussed in the following paragraphs.6
Normal tau binds to tubulin and stabilizes microtubule fibrils in
neurons, thereby facilitating neurite outgrowth. When tau becomes
hyperphosphorylated, it binds to other normal tau proteins, which
leads to aggregation.12Tau hyperphosphorylation in the central
nervous system (CNS) is common after TBI and other brain in-
juries.13TBI can cause normal tau to dissociate from tubulin,
thereby exposing multiple phosphorylation sites.14Hyperpho-
sphorylated tau is no longer able to bind totubulin, and translocates
from the axon to the neuron soma.12A primary reason for this
translocation is that normal tau is soluble, whereas hyperpho-
sphorylated tau becomes insoluble, therefore favoring a paired
helicalfilament arrangement thatistoolargetofunctioninaxons.13
The paired helical arrangement also leads to poor clearance of
hyperphosphorylated tau from the neuron.14Accumulation of in-
soluble tau within neurons contributes to the development of tau
oligomers.15Tau oligomers are granular intracellular buildups of
mutated tau, which precede the development of NFTs.14When tau
phosphatases can no longer dephosphorylate oligomers efficiently,
NFTs grow and eventually mature.16NFT maturation involves the
NFTs can spread to surrounding at-risk neurons through trans-syn-
aptic propagation or extracellular secretion asdepicted in Figure 1.18
Propagation can occur by direct seeding of tau oligomers into the
lipid rafts of cell membranes, thus increasing cell permeability and
behavioral and motor symptoms begin to surface in patients.14A
results in the disruption of tau binding to tubulin. Subsequent hyperphosphorylation of tau leads to formation of tau oligomers in the
neuronal soma. Eventually, neurofibrillary tangles form and are secreted into the extracellular milieu or spread to other neurons via
trans-synaptic propagation. Concurrent with axonal shearing, traumatic brain injury can cause a rapid blood pressure spike resulting in
blood–brain barrier disruption. The disruption leads to an inflammatory cascade as well as microglia and astrocyte activation. Microglia
and astrocyte activation in conjunction with tauopathy contribute to the pathology of chronic traumatic encephalopathy.
Traumatic brain injury can lead to diffuse traumatic axonal injury and blood–brain barrier disruption. Shearing of axons
1130 LUCKE-WOLD ET AL.
likely reason for the symptomatic changes is that NFTs cause neu-
rons to become de-innervated, in part, because of decreased neurite
outgrowth, which ultimately leads to neuronal death.15
Wild-type TDP43 is a nuclear RNA/DNA binding protein that
regulates the transcription of thousands of genes.19TDP43 is pre-
causes an upregulation of Ca2+-permeable a-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid (AMPA) receptors, which in turn
lead to carboxy-terminal-cleaved TDP43 fragments.21These frag-
ments translocate to the cytosol, mediated in part by the process of
representative of several neurodegenerative diseases including:
Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral scle-
rosis, and CTE.20Aggregates sequester RNA leading to pronounced
neurotoxicity.21One mechanism by which neurotoxicity occurs is
TDP43 aggregate-induced misfolding of Cu/Zn superoxide dis-
mutase (SOD1), which predisposes surrounding cells to free-radical
damage.20Associated clinical symptoms of TDP43 pathology in-
clude cognitive and motor impairment.21Cognitive impairment may
take the form of apathy, poor impulse control, and lack of overall
executive judgment.22It has yet to be determined exactly how
TDP43 aggregates coincide and interact with NFTs to produce the
wide spectrum of clinical CTE presentation seen in patients.18
Astrocytes in a healthy brain provide a supporting role for
neurons.23If brain injury occurs, astrocytes become responsive by
increasing expression of a microfilament known as glial fibrillary
acidic protein (GFAP), while simultaneously releasing cytokines
that activate nearby neurons to increase nociceptive receptivity.24
brain recovery.23Blast-induced TBI (bTBI), in particular, causes
increased astrocyte activation and GFAP levels within 24h post-
injury.25Peripheral GFAP is absorbed and sequestered from the
plasma immediately following bTBI, leading to an initial decrease
in serum levels at 6h, but GFAP is subsequently increased by
astrocyte size, number, and motility that primarily occurs in the
white matter following brain or spinal injury.24The activation is
most pronounced in the corpus callosum, motor, and somatosensory
cortex leading to symptoms of increased impulsive behavior and
cognitive dysfunction.25One mechanism by which astrocytes are
activated following brain injury is microglia-mediated crosstalk via
pro-inflammatory cytokines.24These immune cells release inter-
astrocytes, thereby inducing astrocytes to release reactive oxygen
species (ROS).27ROS indirectly cause excitotoxicity by decreasing
the ability of astrocytes to uptake glutamate.28This excitotoxicity
was shown to cause changes in exploratory behavior and distinct
motor deficits in mice exposed to cortical impact TBI.29
in healthy brains.30Following repetitive TBI, localized cell death
activates microglia in the striatum and thalamus, which can be
measured by the markers OX6 and CD68.31Activated microglia
have a bushy appearance with thickened processes and enlarged cell
bodies.30Furthermore, the microglia foster the spread of neuroin-
flammation.32Short- term activation of microglia is neuroprotective,
while chronic activation isinvolvedinneurodegeneration.31Chronic
activation becomes more common in an aged brain, accounting in
part for the progressivenatureof neurodegenerative diseases.33Glial
tangles (GT), for example, are prominent in the frontal and temporal
lobes of CTE brains many years after initial injury.3A primary
reason for the persistence of microglia activation is the presence of
diffuse traumatic axonal injury (dTAI).34dTAI can cause the upre-
gulation of surface antigens on microglia, which ultimately triggers
the release of inflammatory cytokines.32Sensorimotor behavioral
deficits following dTAI have been reported, possibly as a result of
microglia-induced inflammatory tissue damage.34
Background on Tau
Tau isoforms and tau mutations
The gene responsible for encoding tau is microtubule-associated
protein tau (mapt) on chromosome 17.35After tau is encoded, six
isoforms can form by various splicing of exons 2, 3, or 10 on the
microtubule-binding domain of pre-mRNA.36The exon 10 splice
development, and is found specifically in the central nervous sys-
tem.37The isoforms consist of three (3R) or four (4R) tau repeats
inserted at the carboxyl terminus.38Ideally, the ratio between 3R
occur in the exon 10 splice variant, the ratio is shifted to favor an
increase in the 3R isoforms.37Normally, apolipoprotein E in the
brain helps catalyze the proteolytic breakdown of mutated tau and
restore the ideal 3R to 4R ratio, but the APOe4 allele produces an
apolipoprotein that is ineffective in this reaction.3When mutations
persist, they play an important role in NFT development and the
activation of astrocytes.8The altered tau proteins have widespread
Tau kinase overview
Tau has 79 potential binding sites, and phosphorylation of these
sites plays an important role in embryonic CNS development.40
Thirty functional sites on the normal tau protein can be phos-
phorylated inthe adultbrain asdepicted inFigure 2,butthe amount
of phosphorylation is kept to a minimum by tau phosphatases.41
In the adult brain, tau is regulated through multisite phosphoryla-
tion at serine/threonine residues by proline kinases such as extra-
cellular signal-regulated kinases (ERK1/2), cycline-dependent
kinase 5 (CDK5), and glycogen synthase kinase 3-b (GSK3-b).42
Other non- proline kinases such as protein kinase C (PKC), c-Jun
kinase (JNK), Akt, and various tyrosine kinases play a secondary
role in tau phosphorylation.43Following TBI, tau hyperpho-
sphorylation is increased because of an elevation in kinases com-
pared with phosphatases, as depicted in Figure 3, marking an initial
pathological change that indicates future development of chronic
neurodegeneration.44The key tau kinases are described in Table 1,
and discussed in further detail with relation to changes caused by
TBI in the following paragraphs.
ERK1/2 is dephosphorylated following a single mild TBI.45The
dephosphorylated ERK1/2 triggers apoptosis via caspase3 activa-
tion.46Administration of estrone after TBI triggers ERK1/2 phos-
phorylation and pro-survival.47This hormone warrants further
investigation with regard to its potential role in ameliorating tau
LINKING TRAUMATIC BRAIN INJURY TO CTE 1131
hyperphosphorylation. Estrone may initiate a neuroprotective
priming response that protects against subsequent injury.47Other
kinases, such as p70S6K and mitogen and stress-activated protein
kinase 1, may also be involved in this neuroprotective process.48,49
Facilitation of ERK1/2 via the compound PD90859 can addition-
allyfostercellsurvival after braininjury.50Inadditiontomediating
the complex balance between cell survival and apoptosis, ERK1/2
plays another unique role by regulating the cytoskeleton of acti-
vated astrocytes following TBI.51ERK1/2 is, therefore, important
not only for tau hyperphosphorylation but also in the process of
Following TBI, CDK5 acutely binds to its receptor and activates
a pro-apoptotic cascade.52Furthermore, CDK5 triggers cell-cycle
lation, and phosphorylation. (A) We highlight some of the key regulation sites potentially involved in the pathophysiology of chronic
traumatic encephalopathy (CTE). (B) Each site has a specific antibody of interest that can be used to detect changes in intracellular/
extracellular tau. (C) Deglycosylation allows for conversion of tau tangles into bundles of straight filaments, thus increasing the
accessibility of remaining tau located at microtubule edges. Glycosylation, however, reduces phosphorylation of protein kinase A
(PKA), cycline-dependent kinase 5 (CDK5), and glycogen synthase kinase-3b (GSK3b) decreasing formation of neurofibrillary tangles.
This example shows how post-translational modification of tau can regulate tau phosphorylation and ultimately lead to the development
of neurofibrillary tangles, a hallmark of CTE.
Tau is regulated by multiple biochemical processes including: nitration, glycosylation, ubiquitination, acetylation, sumoy-
1132 LUCKE-WOLD ET AL.
activation and microglia activation following controlled cortical
impact TBI.53The extent and duration of microglia activation
mediated by CDK5 requires further investigation. It is known that
inhibition of CDK5 with the roscovitine derivative, CR8, promotes
neuroprotection and decreased apoptosis after controlled cortical
impact.54Additionally, roscovitine itself can improve cognitive
and motor function in Sprague–Dawley rats after TBI.55CDK5
inhibitors even improve outcome when administered several hours
to days after TBI.56How these inhibitors alter the progression of
tauopathies has yet to be investigated.
Protein kinase B (PKB) and serum and glucocorticoid-regulated
kinase (SGK) are activated following TBI, which both subse-
quently phosphorylate GSK3-b.57,58GSK3-b activation via its
phosphorylation has been linked to apoptosis and tau hyperpho-
sphorylation.59Furthermore, GSK3-b upregulates N-Methyl d-
aspartate (NMDA) receptors following brain injury, causing an
exacerbation of glutamate excitotoxicity.60Inhibition of GSK3-b
consequently reduces apoptosis and the extent of excitotoxicity.61
Humanin is a potential inhibitor of GSK3-b that increases neuro-
protection following brain injury, but further studies are still nee-
ded to elucidate the mechanism of action.62GSK3-b is also
functionally significant in microglial migration, translocation of
cascades following TBI.63GSK3-b may, therefore, be a key target
in discovering the link between acute brain injury and chronic
neurodegeneration, because of its primary roles in both microglia
migration and tau hyperphosphorylation.
The five most common isoforms of PKC (a, d, e, f, g) play
various supporting roles as serine/threonine (Ser/Thr) kinases
throughout multiple tissues in the body.64Activation of specific
PKC isoforms (a, d, and f) is associated with perturbations in tight
junction proteins following brain injury, which ultimately leads to
increased BBB permeability.65The disruption in the BBB further
increases PKC activity, thereby triggering the tau kinase, GSK3-
several days post-injury.67After hyperphosphorylation occurs,
PKCa maintains the phosphorylation changes by inhibiting tau
phosphatases.65PKC prompts signal cascades that work in con-
junction with altered calcium homeostasis to propel the develop-
ment of NFTs.66
Because PKC involvement is intimately
associated with tau hyperphosphorylation and NFT formation, it
seems reasonable to investigate the role of selective PKC inhibi-
tors/activators, such as bryostatin and balonol, in the prevention of
chronic tauopathies such as CTE.68,69
is increased, and the phosphatase activity is decreased, hyperphosphorylation persists and can result in the formation of neurofibrillary
tangles. Neurofibrillary tangles contribute to poor outcome by disrupting axonal transport and eventually causing the hierarchical spread
of neurodegeneration. Neurodegeneration ultimately causes the classic symptoms seen in patients suspected of having chronic traumatic
Neurofibrillary tangle formation involves an imbalance between tau kinase and tau phosphatase activity. If tau kinase activity
LINKING TRAUMATIC BRAIN INJURY TO CTE1133
JNK is increased in damaged axons following TBI.70JNK ac-
tivity is also markedly increased in neurons and astrocytes of the
hippocampus following TBI.71JNK signaling can cause post-
traumatic cellular damage within the brain following injury.70JNK
additionally may phosphorylate p53, which enhances neuronal
autophagy.72When JNK is inhibited, the extent of abnormal tau
hyperphospharylation is lessened.70Furthermore, glucagon has
been used to inhibit JNK signaling immediately after TBI, causing
a decrease in intracranial cerebrovasodilation.73Maintaining JNK
signaling within a tightly controlled range is not only important for
tau regulation but also for maintaining blood flow to the brain
Akt produces an interesting effect following brain injury, by
phosphorylating tau at Ser212, but also inhibiting GSK3-b.75
GSK3-b activation may, therefore, be necessary for initial tau hy-
perphosphorylation; however, Akt activity maintains hyperpho-
sphorylation at later time points.43By inhibiting GSK3-b, it is
thought that Akt triggers an antiapoptotic pathway allowing for
damaged cells to survive and propagate NFTs.75If Akt is inhibited,
cell death will occur.76Histone deacetylase inhibitors, such as
scriptaid, prevent the dephosphorylation of Akt, and, therefore,
increase the number of surviving neurons after TBI.77Akt regu-
lation warrants further investigation to tease out the level of acti-
vation that is necessary for maintaining neuroprotective properties
while avoiding the spread of NFTs.
Two phosphatases, protein phosphatase 1 and 2A, are respon-
sible for maintaining tau in a non-hyperphosphorylated state.41If
these two phosphatases become dysfunctional or decreased, the
hyperphosphorylated tau is quickly ubiquitinated, which then pre-
disposes the neuron to increased NFT formation.78TBI can cause a
decrease in tau phosphatases.79In particular, protein phosphatase
2A is decreased in the hippocampus for several weeks post-TBI,
which results in dysfunctional hippocampus plasticity.80Tau
phosphatase activity must drop by half before NFTs will begin to
develop.78Compounds that increase tau phosphatases, such as
sodium selenate, may prove promising in slowing the progression
Although the postmortem pathology of CTE has been well
described, the mechanism by which acute TBI leads to initial tau
hyperphosphorylation and the eventual development of neurofi-
was only recently reintroduced into the medical literature in 2005,
the link between TBI and CTE being associational rather than
mechanistic at this point, the growing prevalence of this disease
among soldiers, football players, wrestlers, and other athletes
exposed to brain injuries increases the urgency for finding a
causative mechanism, and also for locating pharmacological
targets for treating this devastating disease. In the following
paragraphs, we discuss a few molecular pathways previously
Table 1. List of Tau Kinases and the Physiologic Roles in which They Function, also Highlighting
if the Overall Levels of these Kinases Are Altered by Traumatic Brain Injury (TBI)
Kinase name Site of regulationPhysiological role
kinase 5 (CDK5)
Phosphorylation of threonine-x-
Important role in growth factor
signaling, cell survival,
Plays a role in neural development,
pain signaling, and sensory
Implicated in neuronal development,
glucose homeostasis, and body
Binding to CDK Receptor 1 or
CDK Receptor 2
kinase 3-b (GSK3-b)
Requires priming kinase to
phosphorylate a substrate prior
to phosphorylation at tyrosine-216.
Phosphorylation at serine-9,
however, hides the active site
3 categories based on binding at
C-terminal: conventional requires
diacylglycerol and calcium for
activation, novel requires
diacylglycerol, and atypical does
not require calcium or diacylglycerol.
Once active, the receptors for
activated C-kinase bind PKC and help
translocate it to the plasma membrane
Diphosphorylation of the threonine-
Protein kinase C (PKC)
PKC activity is involved with learning
and memory, regulation of
transcription, controlling cell growth,
and mediating immune responses
c-Jun kinase (JNK) JNKs participate in multiple stress
cascades, the inflammation response,
and reactive oxygen species formation
Akt plays a role in apoptosis, cellular
metabolism, and cell migration
AktAkt binds to phosphatidylinositol
(3,4,5)-triphosphate on the cell
membrane and then is phosphorylated
at threonine 308 by phosphoinosotide
1134LUCKE-WOLD ET AL.
associated with other forms of brain injury that warrant further
investigation following TBI.
Endoplasmic reticulum (ER) stress
The ER is responsible for the correct folding and sorting of
proteins.83Following brain injury, the ER becomes dysfunctional,
as is evidenced by changes in bound intracellular calcium, leading
to the accumulation of unfolded proteins within the cell.84The
increase in unfolded proteins is known as the ‘‘ER stress re-
of the ER stress response.86Three arms of the ER stress response
(protein kinase-like ER kinase [PERK], inositol requiring enzyme
1a [IRE1a], and activating transcription factor 6 [ATF6]) regulate
the amount of pro-apoptotic activity following injury.83All three
arms affect the protein expression of C/EBP-homologous protein
(CHOP).84CHOP is noteworthy for its ability to trigger apoptosis
via the activation of caspase12.86If CHOP is maintained below
threshold by the PERK arm, neuronal apoptosis does not occur.85
When CHOP is pushed beyond threshold through activation of the
IRE1a and ATF6 arms, neuronal apoptosis does occur, and tau
hyperphosphorylation results from GSK3-b.87Furthermore, two
downstream targets of the ATF6 arm of the ER stress pathway are
mitogen-activated protein kinase (MAPK) and JNK, which may
subsequently be involved in tau hyperphosphorylation as well.88In
light of these findings, it may prove beneficial to utilize a phar-
macological agent that attenuates the ER stress response in a model
of TBI. Salubrinal can increase activity of the neuroprotective
PERK arm of the ER stress response and inhibit the pro-apoptotic
activity of the IRE1a arm of the ER stress response.89Because
GSK3-b and caspase12 are increased following brain injury, it may
also be worth investigating the GSK3-b peptide inhibitors, L803-
mts and TDZD-8, and the role they may play in preventing the
development of NFTs.87,90
Glutamate excitotoxicity is triggered following brain injury,
and results in elevated intracellular calcium, formation of ROS,
and mitochondrial failure.91Ischemia and other forms of brain
injury can cause an increase in calcium that activates a-calcium/
calmodulin protein kinase II, leading to memory impairment via
increased AMPA receptor activity in the hippocampus.92The
increased calcium also leads to intracellular accumulation in
neuronal mitochondria, making the organelle dysfunctional.91
Activated microglia and astrocytes concurrently release inter-
leukin-6, which triggers a further increase in intracellular cal-
cium within neurons and sensitizes NMDA receptors.93
Sensitized NMDA receptors promote auxiliary excitotoxicity
and foster the release of ROS from the mitochondria, which
can eventually cause neuronal destruction.28Caspase3, a pro-
apoptotic factor, is increased following glutamate- induced mi-
tochondria dysfunction.86Caspase3 can cause tau cleavage and
predisposes the neuron to NFT development.87To stem the tide
of neuronal destruction and progressive tau changes, it seems
fitting to investigate compounds that are known to decrease the
amount of ROS such as the nicotinamide adenine dinucleotide
phosphate (NADPH)-oxidase inhibitor, apocynin.27Further-
more, targeting mitochondrial dysfunction through p38 inhibi-
tors may also prove beneficial following head trauma.94By
targeting key downstream pathways of glutamate excitotoxicity,
it may be possible to alleviate the potential progression to neu-
Microglial and astrocyte regulators
Neurotrauma can result in a dynamic equilibrium between
classically activated (M1) and alternatively activated (M2) mi-
croglia.31M1 microglia are pro-inflammatory, whereas M2 mi-
croglia are anti-inflammatory.34Targeting the activation of M2
microglia immediately following injury may prove beneficial in
preventing neurodegeneration.95Alternatively, acutely inhibiting
M1 microglia with the noncompetitive cholinesterase inhibitor,
donepezil, has also decreased neuroinflammation and apoptosis
after TBI.96Similarly, neurotrauma triggers two distinct responses,
pro-survival or apoptosis, in activated astrocytes, depending upon
the extent and duration of injury.25If astrocyte activation extends
several days post-injury, it was found that nitration of tau occurs,
which may lead to a more rapid development of NFTs.97Further-
more, mutations in tau may be occurring in activated astrocytes,
resulting in tau oligomers being subsequently secreted into the
extracellular milieu.17Future studies are needed to characterize the
time course of astrocyte activation following TBI, and, more im-
portantly, at what point it is ideal to inhibit astrocyte activation.
Clinical Relevance and Conclusions
The Veterans Affairs Healthcare System reported that patients
exposed to repetitive blast waves have quantitative electroen-
cephalogram changes that are comparable to concussive injury.98
Similarly, the detection of repetitive concussions in athletes has
increased significantly over the past 20 years.10The duration
between injuries may account for why certain individuals de-
velop rapidly progressive neurodegeneration and increased
phospho-tau expression.13The Department of Defense has re-
cently invested $700,000,000 into improving clinical diagnosis
and care for the 266,810 bTBI patients who were injured from
2001 onwards.98Likewise, the National Football League has
recently organized a new medical committee to investigate the
issue of TBI, and has started a multiprong approach for making
football safer for the players.99Increased investigation into un-
derstanding the pathology of CTE will hopefully aid in pre-
mortem diagnosis, as well as finding viable treatment options.
The pathways mentioned in this review (ER stress, glutamate
excitotoxicty, and microglia and astrocyte modulation) appear
promising in understanding the link between acute bTBI and
CTE development. Discovering the process of tau hyperpho-
sphorylation and NFT development following TBI will likely
provide a key for unlocking the unknown mysteries of similar
progressive neurodegenerative diseases.
We thank Ann Noelle Lucke-Wold for her help in editing this
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Charles Lee Rosen, MD, PhD
Department of Neurosurgery
West Virginia University School of Medicine
One Medical Center Drive
Suite 4300, Health Sciences Center
PO Box 9183
Morgantown, WV 26506-9183
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