Induction of a transmissible tau pathology by traumatic brain injury.
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ABSTRACT:
SUBMITTER: Zanier ER
PROVIDER: S-EPMC6113646 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
Induction of a transmissible tau pathology by traumatic brain injury.
Zanier Elisa R ER Bertani Ilaria I Sammali Eliana E Pischiutta Francesca F Chiaravalloti Maria Antonietta MA Vegliante Gloria G Masone Antonio A Corbelli Alessandro A Smith Douglas H DH Menon David K DK Stocchetti Nino N Fiordaliso Fabio F De Simoni Maria-Grazia MG Stewart William W Chiesa Roberto R
Brain : a journal of neurology 20180901 9
Traumatic brain injury is a risk factor for subsequent neurodegenerative disease, including chronic traumatic encephalopathy, a tauopathy mostly associated with repetitive concussion and blast, but not well recognized as a consequence of severe traumatic brain injury. Here we show that a single severe brain trauma is associated with the emergence of widespread hyperphosphorylated tau pathology in a proportion of humans surviving late after injury. In parallel experimental studies, in a model of ...[more]
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Project description:[18F]AV-1451 (aka 18F-Flortaucipir, [18F]T807) was developed for positron-emission tomography (PET) imaging of paired helical filaments of hyperphosphorylated tau, which are of interest in a range of neuropathologies, including traumatic brain injury (TBI). Magnetic resonance imaging (MRI) techniques like diffusion tensor imaging (DTI) and resting state functional connectivity assess structural and functional characteristics of the brain, complementing the molecular information that can be obtained by PET. The goal herein was to explore the utility of such multi-modal imaging in a case series based on a population of TBI subjects. This study probes the interrelationship between tau deposition, white matter integrity, and gray matter functional connectivity across the spectrum of TBI. Nineteen subjects (11 controls, five former contact sports athletes, one automotive accident, and two with military-related injury) underwent [18F]AV-1451 PET and magnetic resonance scanning procedures. [18F]AV-1451 distribution volume ratio (DVR) was estimated using the Logan method and the cerebellum as a reference region. Diffusion tractography images and fractional anisotropy (FA) images were generated using diffusion toolkit and FSL. Resting-state functional MRI (fMRI) analysis was based on a graph theory metric, namely weighted degree centrality. TBI subjects showed greater heterogeneity in [18F]AV-1451 DVR when compared with control subjects. In a subset of TBI subjects, areas with high [18F]AV-1451 binding corresponded with increased FA and diminished white matter tract density in DTI. Functional MRI results exhibited an increase in functional connectivity, particularly among local connections, in the areas where tau aggregates were more prevalent. In a case series of a diverse group of TBI subjects, brain regions with elevated tau burden exhibited increased functional connectivity as well as decreased white matter integrity. These findings portray molecular, microstructural, and functional corollaries of TBI that spatially coincide and can be measured in the living human brain using noninvasive neuroimaging techniques.
| S-EPMC6857466 | biostudies-literature
Project description:The misfolding and aggregation of tau protein into neurofibrillary tangles is the main underlying hallmark of tauopathies. Most tauopathies have a sporadic origin and can be associated with multiple risk factors. Traumatic brain injury (TBI) has been suggested as a risk factor for tauopathies by triggering disease onset and facilitating its progression. Several studies indicate that TBI seems to be a risk factor to development of Alzheimer disease and chronic traumatic encephalopathy, because there is a relationship of TBI severity and propensity to development of these illnesses. In this study, we evaluated whether moderate to severe TBI can trigger the initial formation of pathological tau that would induce the development of the pathology throughout the brain. To this end, we subjected tau transgenic mice to TBI and assessed tau phosphorylation and aggregation pattern to create a spatial heat map of tau deposition and spreading in the brain. Our results suggest that brain injured tau transgenic mice have an accelerated tau pathology in different brain regions that increases over time compared with sham mice. The appearance of pathological tau occurs in regions distant to the injury area that are connected synaptically, suggesting dissemination of tau aggregates. Overall, this work posits TBI as a risk factor for tauopathies through the induction of tau hyperphosphorylation and aggregation.
| S-EPMC6921297 | biostudies-literature
Project description:Tau pathology associated with chronic traumatic encephalopathy has been documented in the brains of individuals with a history of repetitive mild traumatic brain injury (r-mTBI). At this stage, the pathobiological role of tau in r-mTBI has not been extensively explored in appropriate pre-clinical models. Here, we describe the acute and chronic behavioral and histopathological effects of single and repetitive mild TBI (five injuries given at 48?h intervals) in young adult (3 months old) hTau mice that express all six isoforms of hTau on a null murine tau background. Animals exposed to r-mTBI showed impaired visuospatial learning in the Barnes maze test that progressively worsened from two weeks to 12 months post-injury, which was also accompanied by significant deficits in visuospatial memory consolidation at 12 months post-injury. In contrast, only marginal changes were observed in visuospatial learning at six and 12 months after single mTBI. Histopathological analyses revealed that hTau mice developed axonal injury, thinning of the corpus callosum, microgliosis and astrogliosis in the white matter at acute and chronic time points after injury. Tau immunohistochemistry and enzyme-linked immunosorbent assay data suggest, however, only transient, injury-dependent increases in phosphorylated tau in the cerebral cortex beneath the impact site and in the CA1/CA3 subregion of the hippocampus after single or r-mTBI. This study implicates white matter degeneration as a prominent feature of survival from mTBI, while the role of tau pathology in the neuropathological sequelae of TBI remains elusive.
| S-EPMC6354615 | biostudies-literature
Project description:Traumatic brain injury (TBI) is associated with widespread tau pathology in about 30% of patients surviving late after injury. We previously found that TBI in mice induces the formation of an abnormal form of tau (tauTBI) which progressively spreads from the site of injury to remote brain regions. Intracerebral inoculation of TBI brain homogenates into naïve mice induced progressive tau pathology, synaptic loss and late cognitive decline, suggesting a pivotal role of tauTBI in post-TBI neurodegeneration. However, the possibility that tauTBI was a marker of TBI-associated neurodegeneration rather than a toxic driver of functional decline could not be excluded. Here we employed the nematode C. elegans as a biosensor to test the pathogenic role of TBI generated tau. The motility of this nematode depends on efficient neuromuscular transmission and is exceptionally sensitive to the toxicity of amyloidogenic proteins, providing a tractable model for our tests. We found that worms exposed to brain homogenates from chronic but not acute TBI mice, or from mice in which tauTBI had been transmitted by intracerebral inoculation, had impaired motility and neuromuscular synaptic transmission. Results were similar when worms were given brain homogenates from transgenic mice overexpressing tau P301L, a tauopathy mouse model, suggesting that TBI-induced and mutant tau have similar toxic properties. P301L brain homogenate toxicity was similar in wild-type and ptl-1 knock-out worms, indicating that the nematode tau homolog protein PTL-1 was not required to mediate the toxic effect. Harsh protease digestion to eliminate the protein component of the homogenates, pre-incubation with anti-tau antibodies or tau depletion by immunoprecipitation, abolished the toxicity. Homogenates of chronic TBI brains from tau knock-out mice were not toxic to C. elegans, whereas oligomeric recombinant tau was sufficient to impair their motility. This study indicates that tauTBI impairs motor activity and synaptic transmission in C. elegans and supports a pathogenic role of tauTBI in the long-term consequences of TBI. It also sets the groundwork for the development of a C. elegans-based platform for screening anti-tau compounds.
| S-EPMC8039186 | biostudies-literature
Project description:Mild traumatic brain injury accounts for the majority of head injuries and has been correlated with neurodegeneration and dementia. While repetitive mild traumatic brain injury is highly correlated to neurodegeneration, the correlation of a single mild traumatic brain injury with neurodegeneration is still unclear. Because tau aggregates are the main form of mild traumatic brain injury induced pathology, toxic forms of tau protein most likely play a role in the development of post-mild traumatic brain injury neurodegeneration. Therefore, it becomes crucial to characterize the properties of soluble tau aggregates in single versus repetitive mild traumatic brain injury. Herein, we isolated tau oligomers from wild-type mice exposed to single or repetitive mild traumatic brain injury and characterized the tau aggregates at functional, biochemical and biophysical levels. We demonstrated that single versus repetitive mild traumatic brain injuries frequencies lead to the formation of different tau oligomeric polymorphisms. These polymorphisms express different long-term potentiation impairment potencies, toxicity potentials, morphologies and strain indicating properties. To our knowledge, this is the first evidence that soluble tau oligomers derived from single versus repetitive mild traumatic brain injuries form distinct polymorphisms that possibly correlate with the risk of neurodegeneration after mild traumatic brain injury.
| S-EPMC6777515 | biostudies-literature
Project description:Traumatic brain injury can lead to the neurodegenerative disease chronic traumatic encephalopathy. This condition has a clear neuropathological definition but the relationship between the initial head impact and the pattern of progressive brain pathology is poorly understood. We test the hypothesis that mechanical strain and strain rate are greatest in sulci, where neuropathology is prominently seen in chronic traumatic encephalopathy, and whether human neuroimaging observations converge with computational predictions. Three distinct types of injury were simulated. Chronic traumatic encephalopathy can occur after sporting injuries, so we studied a helmet-to-helmet impact in an American football game. In addition, we investigated an occipital head impact due to a fall from ground level and a helmeted head impact in a road traffic accident involving a motorcycle and a car. A high fidelity 3D computational model of brain injury biomechanics was developed and the contours of strain and strain rate at the grey matter-white matter boundary were mapped. Diffusion tensor imaging abnormalities in a cohort of 97 traumatic brain injury patients were also mapped at the grey matter-white matter boundary. Fifty-one healthy subjects served as controls. The computational models predicted large strain most prominent at the depths of sulci. The volume fraction of sulcal regions exceeding brain injury thresholds were significantly larger than that of gyral regions. Strain and strain rates were highest for the road traffic accident and sporting injury. Strain was greater in the sulci for all injury types, but strain rate was greater only in the road traffic and sporting injuries. Diffusion tensor imaging showed converging imaging abnormalities within sulcal regions with a significant decrease in fractional anisotropy in the patient group compared to controls within the sulci. Our results show that brain tissue deformation induced by head impact loading is greatest in sulcal locations, where pathology in cases of chronic traumatic encephalopathy is observed. In addition, the nature of initial head loading can have a significant influence on the magnitude and pattern of injury. Clarifying this relationship is key to understanding the long-term effects of head impacts and improving protective strategies, such as helmet design.
| S-EPMC5278309 | biostudies-literature
Project description:Diffuse axonal injury (DAI) is a common feature of severe traumatic brain injury (TBI) and may also be a predominant pathology in mild TBI or "concussion". The rapid deformation of white matter at the instant of trauma can lead to mechanical failure and calcium-dependent proteolysis of the axonal cytoskeleton in association with axonal transport interruption. Recently, a proteolytic fragment of alpha-II spectrin, "SNTF", was detected in serum acutely following mild TBI in patients and was prognostic for poor clinical outcome. However, direct evidence that this fragment is a marker of DAI has yet to be demonstrated in either humans following TBI or in models of mild TBI. Here, we used immunohistochemistry (IHC) to examine for SNTF in brain tissue following both severe and mild TBI. Human severe TBI cases (survival <7d; n = 18) were compared to age-matched controls (n = 16) from the Glasgow TBI archive. We also examined brains from an established model of mild TBI at 6, 48 and 72 h post-injury versus shams. IHC specific for SNTF was compared to that of amyloid precursor protein (APP), the current standard for DAI diagnosis, and other known markers of axonal pathology including non-phosphorylated neurofilament-H (SMI-32), neurofilament-68 (NF-68) and compacted neurofilament-medium (RMO-14) using double and triple immunofluorescent labeling. Supporting its use as a biomarker of DAI, SNTF immunoreactive axons were observed at all time points following both human severe TBI and in the model of mild TBI. Interestingly, SNTF revealed a subpopulation of degenerating axons, undetected by the gold-standard marker of transport interruption, APP. While there was greater axonal co-localization between SNTF and APP after severe TBI in humans, a subset of SNTF positive axons displayed no APP accumulation. Notably, some co-localization was observed between SNTF and the less abundant neurofilament subtype markers. Other SNTF positive axons, however, did not co-localize with any other markers. Similarly, RMO-14 and NF-68 positive axonal pathology existed independent of SNTF and APP. These data demonstrate that multiple pathological axonal phenotypes exist post-TBI and provide insight into a more comprehensive approach to the neuropathological assessment of DAI.
| S-EPMC4780426 | biostudies-literature
Project description:Protein citrullination is a calcium-driven post-translational modification proposed to play a causative role in the neurodegenerative disorders of Alzheimer's disease, multiple sclerosis (MS), and prion disease. Citrullination can result in the formation of antigenic epitopes that underlie pathogenic autoimmune responses. This phenomenon, which is best understood in rheumatoid arthritis, may play a role in the chronic dysfunction following traumatic brain injury (TBI). Despite substantial evidence of aberrations in calcium signaling following TBI, there is little understanding of how TBI alters citrullination in the brain. The present investigation addressed this gap by examining the effects of TBI on the distribution of protein citrullination and on the specific cell types involved. Immunofluorescence revealed that controlled cortical impact in rats profoundly up--regulated protein citrullination in the cerebral cortex, external capsule, and hippocampus. This response was exclusively seen in astrocytes; no such effects were observed on the status of protein citrullination in neurons, oligodendrocytes or microglia. Further, proteomic analyses demonstrated that the effects of TBI on citrullination were confined to a relatively small subset of neural proteins. Proteins most notably affected were those also reported to be citrullinated in other disorders, including prion disease and MS. In vivo findings were extended in an in vitro model of simulated TBI employing normal human astrocytes. Pharmacologically induced calcium excitotoxicity was shown to activate the citrullination and breakdown of glial fibrillary acidic protein, producing a novel candidate TBI biomarker and potential target for autoimmune recognition. In summary, these findings demonstrate that the effects of TBI on protein citrullination are selective with respect to brain region, cell type, and proteins modified, and may contribute to a role for autoimmune dysfunction in chronic pathology following TBI.
| S-EPMC4585288 | biostudies-literature
Project description:ImportanceAnnually in the United States, at least 3.5 million people seek medical attention for traumatic brain injury (TBI). The development of therapies for TBI is limited by the absence of diagnostic and prognostic biomarkers. Microtubule-associated protein tau is an axonal phosphoprotein. To date, the presence of the hypophosphorylated tau protein (P-tau) in plasma from patients with acute TBI and chronic TBI has not been investigated.ObjectiveTo examine the associations between plasma P-tau and total-tau (T-tau) levels and injury presence, severity, type of pathoanatomic lesion (neuroimaging), and patient outcomes in acute and chronic TBI.Design, setting, and participantsIn the TRACK-TBI Pilot study, plasma was collected at a single time point from 196 patients with acute TBI admitted to 3 level I trauma centers (<24 hours after injury) and 21 patients with TBI admitted to inpatient rehabilitation units (mean [SD], 176.4 [44.5] days after injury). Control samples were purchased from a commercial vendor. The TRACK-TBI Pilot study was conducted from April 1, 2010, to June 30, 2012. Data analysis for the current investigation was performed from August 1, 2015, to March 13, 2017.Main outcomes and measuresPlasma samples were assayed for P-tau (using an antibody that specifically recognizes phosphothreonine-231) and T-tau using ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification.ResultsIn the 217 patients with TBI, 161 (74.2%) were men; mean (SD) age was 42.5 (18.1) years. The P-tau and T-tau levels and P-tau-T-tau ratio in patients with acute TBI were higher than those in healthy controls. Receiver operating characteristic analysis for the 3 tau indices demonstrated accuracy with area under the curve (AUC) of 1.000, 0.916, and 1.000, respectively, for discriminating mild TBI (Glasgow Coma Scale [GCS] score, 13-15, n = 162) from healthy controls. The P-tau level and P-tau-T-tau ratio were higher in individuals with more severe TBI (GCS, ≤12 vs 13-15). The P-tau level and P-tau-T-tau ratio outperformed the T-tau level in distinguishing cranial computed tomography-positive from -negative cases (AUC = 0.921, 0.923, and 0.646, respectively). Acute P-tau levels and P-tau-T-tau ratio weakly distinguished patients with TBI who had good outcomes (Glasgow Outcome Scale-Extended GOS-E, 7-8) (AUC = 0.663 and 0.658, respectively) and identified those with poor outcomes (GOS-E, ≤4 vs >4) (AUC = 0.771 and 0.777, respectively). Plasma samples from patients with chronic TBI also showed elevated P-tau levels and a P-tau-T-tau ratio significantly higher than that of healthy controls, with both P-tau indices strongly discriminating patients with chronic TBI from healthy controls (AUC = 1.000 and 0.963, respectively).Conclusions and relevancePlasma P-tau levels and P-tau-T-tau ratio outperformed T-tau level as diagnostic and prognostic biomarkers for acute TBI. Compared with T-tau levels alone, P-tau levels and P-tau-T-tau ratios show more robust and sustained elevations among patients with chronic TBI.
| S-EPMC5710183 | biostudies-literature
Project description:Adult male and female Tau-KO flies were inflicted with traumatic brain injury using high-impact trauma device. Brains were dissected at control, 1, 2 and 4 hours post-TBI. Total RNA was extracted from fly brains and 3'mRNA-seq was performed to assess gene expression changes in response to TBI in both sexes. 3 replicates were sequenced for each condition.
2021-07-15 | GSE148939 | GEO