Repetitive Mild Traumatic Brain Injury Augments Tau Pathology and Glial Activation in Aged hTau Mice

Ojo, J. Villegas-del; Mouzon, Benoit; Greenberg, M. Banks; Bachmeier, Corbin; Mullan, Michael; Crawford, Fiona

doi:10.1097/nen.0b013e3182814cdf

Cited by 146 publications

(105 citation statements)

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“…There has been one report of accelerated hyperphosphorylated tau staining, accompanied by an increase in Gallyas silver staining, in aged human tau mice exposed to 5 rmTBIs over a 9-day period and euthanized 21 days after the final injury. 12 However, we found no evidence of increased phospho-tau at either 1 or 30 days after injury in our aged 3xTg-AD mice. There are differences between our study and the study by Mouzon et al 49 We used a different transgenic mouse model (3xTg-AD has a single mutant human tau isoform, but the human tau mouse has all six human tau isoforms), and the trauma model used in the human tau study appears to be more severe than our model, with traumatic axonal injury evidenced by APP accumulation in the corpus callosum in their model.…”

Section: Rmtbi Does Not Induce Amyloid or Tau Pathology In 3xtg-ad Micecontrasting

confidence: 64%

“…11 There has been difficulty reproducing tau pathology in rodents after rmTBI, and to date the only study that has seen a chronic (21 days after TBI) increase in hyperphosphorylated tau after rmTBI has required the use of aged tau transgenic mice to observe an effect. 12 In this study, we examine changes to the neuronal structure and brain pathology after a single mTBI or rmTBI. We are especially interested in changes that can occur after mTBI that may explain the changes in brain function after concussion.…”

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confidence: 99%

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Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Winston

Noël

Neustadtl

et al. 2016

The American Journal of Pathology

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Mild traumatic brain injury (mTBI) is an emerging risk for chronic behavioral, cognitive, and neurodegenerative conditions. Athletes absorb several hundred mTBIs each year; however, rodent models of repeat mTBI (rmTBI) are often limited to impacts in the single digits. Herein, we describe the effects of 30 rmTBIs, examining structural and pathological changes in mice up to 365 days after injury. We found that single mTBI causes a brief loss of consciousness and a transient reduction in dendritic spines, reflecting a loss of excitatory synapses. Single mTBI does not cause axonal injury, neuroinflammation, or cell death in the gray or white matter. Thirty rmTBIs with a 1-day interval between each mTBI do not cause dendritic spine loss; however, when the interinjury interval is increased to 7 days, dendritic spine loss is reinstated. Thirty rmTBIs cause white matter pathology characterized by positive silver and Fluoro-Jade B staining, and microglial proliferation and activation. This pathology continues to develop through 60 days, and is still apparent at 365 days, after injury. However, rmTBIs did not increase b-amyloid levels or tau phosphorylation in the 3xTg-AD mouse model of Alzheimer disease. Our data reveal that single mTBI causes a transient loss of synapses, but that rmTBIs habituate to repetitive injury within a short time period. rmTBI causes the development of progressive white matter pathology that continues for months after the final impact. (Am J Pathol 2016, 186: 552e567; http://dx.doi.org/ 10.1016/j.ajpath.2015 Athletes participating in contact sports are at high risk of exposure to large numbers of concussive and subconcussive mild traumatic brain injuries (mTBIs). Recent studies using head impact telemetry systems have begun to reveal how many head impacts an individual football player can receive in the process of playing his or her sport. In a study of high school football players, the number of helmet impacts >20 g recorded in a single season ranged from a low of 226 (average, 4.7 per session) to a high of 1855 (average, 38.6 per session). 1 Most of these impacts do not result in the clinical diagnosis of a concussion; however, it is not known if the cumulative effects of these impacts can result in increased damage to the brain. mTBI has been extensively modeled in mice and rats. 2 Most of these rodent models use fewer than five mTBIs, and report adverse events, including intracerebral bleeding, skull fractures, severe axonal injury, neuronal cell death, and increased mortality.

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Section: Rmtbi Does Not Induce Amyloid or Tau Pathology In 3xtg-ad Micecontrasting

confidence: 64%

mentioning

confidence: 99%

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Winston

Noël

Neustadtl

et al. 2016

The American Journal of Pathology

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“…This is common to preclinical mTBI models, as mTBI‐dependent tau pathology has been difficult to model 48. This could be due to differences in injury models,49 injury severity,50 injury frequency,15 age51 at exposure, species used (pig, rat, mice, gerbil), and genetic background (e.g., whether the animal is expressing wild type or human (or mutant) tau or amyloid). In a recent review, we discussed the current literature and the difficulties and challenges of developing in vivo TBI experimental paradigms to explore the link between repetitive head trauma with a focus on tau‐dependent changes 48.…”

Section: Discussionmentioning

confidence: 99%

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Mouzon

Bachmeier

Ojo

et al. 2017

Ann Clin Transl Neurol

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ObjectiveExposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long‐term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of mTBI in these models. This study provides the first account of lifelong neurobehavioral and histological consequences of repetitive mTBI providing unique insight into the constellation of evolving and ongoing pathologies with late survival.MethodsMale C57BL/6J mice (aged 2–3 months) were exposed to either single or repetitive mild TBI or sham procedure. Thereafter, animals were monitored and assessed at 24 months post last injury for measures of motor coordination, learning deficits, cognitive function, and anxiety‐like behavior prior to euthanasia and preparation of the brains for detailed neuropathological and protein biochemical studies.ResultsAt 24 months survival animals exposed to r‐mTBI showed clear evidence of learning and working memory impairment with a lack of spatial memory and vestibule‐motor vestibulomotor deficits compared to sham animals. Associated with these late behavioral deficits there was evidence of ongoing axonal degeneration and neuroinflammation in subcortical white matter tracts. Notably, these changes were also observed after a single mTBI, albeit to a lesser degree than repetitive mTBI.InterpretationIn this context, our current data demonstrate, for the first time, that rather than an acute, time limited event, mild TBI can precipitate a lifelong degenerative process. These data therefore suggest that successful treatment strategies should consider both the acute and chronic nature of mTBI.

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“…In another study, which used mice that expressed all 6 isoforms of wild-type human tau protein, increased phosphorylation of tau was found in mice that were exposed to repetitive mTBI but not to a single mTBI. 106 Another mouse model of brain trauma was able to recapitulate several features of CTE following blast injury, similar to those suffered by US military veterans. 46 Two weeks after blast exposure, mice demonstrated phosphorylated tauopathy, myelinated axonopathy, chronic inflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage.…”

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Sports-related brain injuries: connecting pathology to diagnosis

Pan¹,

Connolly²,

Dangelmajer³

et al. 2016

FOC

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Neurosurg Focus 40 (4):E14, 2016M any sports-related brain injuries involve mild traumatic brain injuries (mTBIs), which result from physical blows to the head sustained over a period of time. Sports associated with an increased risk of head injury include American football, ice hockey, soccer, rugby, the martial arts, boxing, and bicycling. 21,90 These injuries are often unrecognized, undiagnosed, or underreported, which reflects the fact that this is a growing medical concern, often labeled a "silent epidemic." 8,66 Chronic exposure to mild brain injuries can result in long-term neurological consequences and represents a spectrum of disorders. The most remarkable outcome of mTBI is termed chronic traumatic encephalopathy (CTE), a clinical syndrome that is associated with neurodegeneration and behavioral, cognitive, and/or motor deficits. Although this disease has distinct pathological features, CTE is considered a diagnosis of exclusion because only postmortem biopsies can confirm the diagnosis. Therefore, new diagnostic methods need to be developed to: 1) inform patients of a definitive diagnosis, 2) better understand the epidemiology and risk factors of the disease, and 3) implement intervention programs to prevent any potential long-term complications. This review examines how understanding the pathology and molecular changes associated with repeated head trauma can lead to the discovery of novel imaging techniques and biomarkers. Mild Traumatic Brain Injury and CTEChronic traumatic encephalopathy has evolved from the so-called punch-drunk syndrome, which was used to describe a distinct neuropsychiatric condition that seemed to affect boxers, eventually becoming known as dementia pugilistica during the 1920s and 1930s. Symptoms such ABBrEvIATIoNs AD = Alzheimer's disease; APOE = apolipoprotein E; ASL = arterial spin labeling; BBB = blood-brain barrier; BOLD = blood oxygen level-dependent; CA = cornu ammonis; CTE = chronic traumatic encephalopathy; DTI = diffusion tensor imaging; FA = fractional anisotropy; fMRI = functional MRI; GFAP = glial fibrillary acidic protein; GRE = gradient recall echo; miRNA = microRNA; MRS = MR spectroscopy; mTBI = mild traumatic brain injury; NFL = National Football League; NFT = neurofibrillary tangle; NINDS = National Institute of Neurological Disorders and Stroke; NSE = neuron-specific enolase; p-tau = phosphorylated tau; SWI = susceptibility-weighted imaging; TDP-43 = TAR DNA-binding protein 43;18 F-FDDNP = 2-(1-{6- [(2-[fluorine-18] Brain injuries are becoming increasingly common in athletes and represent an important diagnostic challenge. Early detection and management of brain injuries in sports are of utmost importance in preventing chronic neurological and psychiatric decline. These types of injuries incurred during sports are referred to as mild traumatic brain injuries, which represent a heterogeneous spectrum of disease. The most dramatic manifestation of chronic mild traumatic brain injuries is termed chronic traumatic encephalopathy, which is associated with profo...

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Repetitive Mild Traumatic Brain Injury Augments Tau Pathology and Glial Activation in Aged hTau Mice

Cited by 146 publications

References 61 publications

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Sports-related brain injuries: connecting pathology to diagnosis

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