Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowthviatheir transfer into neurons

The FASEB Journal, Год журнала: 2017, Номер 32(1), С. 512 - 528

Опубликована: Сен. 21, 2017

Neuronal inflammation is the characteristic pathologic change of acute neurologic impairment and chronic traumatic encephalopathy after brain injury (TBI). Inhibiting excessive inflammatory response essential for improving outcome. To clarify regulatory mechanism microglial exosomes on neu-ronal in TBI, we focused studying impact exosomal miRNAs injured neurons this research. We used a repetitive (r)TBI mouse model harvested extracts from to phase TBI treat cultured BV2 microglia vitro. The were collected miRNA microarray analysis, which showed that expression level miR-124-3p increased most apparently miRNAs. found promoted anti-inflamed M2 polarization microglia, inhibited neuronal scratch-injured neurons. Further, mammalian target rapamycin (mTOR) signaling was implicated as being involved regulation by Gene Ontology Kyoto Encyclopedia Genes Genomes pathway analyses. Using mTOR activator MHY1485 confirmed inhibitory effect exerted suppressing activity signaling. PDE4B predicted be gene analysis. proved it directly targeted with luciferase reporter assay. overexpressed lentivirus transfection system, suggested suppressed mainly through inhibiting PDE4B. In addition, neurite outgrowth scratch injury, characterized an increase number branches total length, decreasedexpressiononRhoAand neurodegenerative proteins [Aß-peptide p-Tau]. It also improved outcome neuro-inflammation mice rTBI. Taken together, can inhibit contribute via their transfer into these effects targeting PDE4B, thus Therefore, could promising therapeutic interventions TBI. manipulated may provide novel therapy other diseases.—Huang, S., Ge, X., Yu, J., Han, Z., Yin, Li, Y., Chen, F., Wang, H., Zhang, Lei, P. Increased following inhibits contributes FASEB J. 32, 512-528 (2018). www.fasebj.org

Язык: Английский

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Blood Biomarkers for Brain Injury in Concussed Professional Ice Hockey Players

JAMA Neurology, Год журнала: 2014, Номер 71(6), С. 684 - 684

Опубликована: Март 13, 2014

Lack of objective biomarkers for brain damage hampers acute diagnosis and clinical decision making about return to play after sports-related concussion.To determine whether concussion is associated with elevated levels blood biochemical markers injury the central nervous system assess plasma these predict in professional ice hockey players concussion.Multicenter prospective cohort study involving all 12 teams top league Sweden, Swedish Hockey League. Two hundred eighty-eight from contesting during 2012-2013 season consented participate. All underwent preseason baseline testing regarding assessment measures. Forty-seven 2 sampling prior start season. Thirty-five had a September 13, 2012, January 31, 2013; players, 28 repeated at 1, 12, 36, 144 hours when returned play.Total tau, S-100 calcium-binding protein B, neuron-specific enolase concentrations serum were measured.Concussed increased axonal biomarker total tau(median, 10.0 pg/mL; range, 2.0-102 pg/mL) compared values (median, 4.5pg/mL; 0.06-22.7 (P < .001). The astroglial B also concussion(median, 0.075 μg/L; 0.037-0.24 μg/L) (median,0.045 0.005-0.45 highest tau measured immediately concussion, they decreased rehabilitation. No significant changes detected 6.5 range,3.45-18.0 postconcussion 6.1 3.6-12.8 = .10).Sports-related injury. This can be monitored using biomarkers, which may developed into tools guide sport physicians medical counseling athletes return-to-play decisions.

Язык: Английский

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Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model

Brain, Год журнала: 2017, Номер 141(2), С. 422 - 458

Опубликована: Дек. 2, 2017

The mechanisms underpinning concussion, traumatic brain injury, and chronic encephalopathy, the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in acute-subacute period after mild closed-head impact injury found astrocytosis, myelinated axonopathy, microvascular perivascular neuroinflammation, phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral that uses momentum transfer to induce head acceleration. Unanaesthetized mice subjected unilateral exhibited abrupt onset, transient course, rapid resolution concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor balance impairments, neurobehavioural deficits. Experimental was associated with blood–brain barrier disruption, microgliosis (with activation triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, tauopathy cerebral cortex ipsilateral subjacent impact. Phosphorylated detected axons 24 h, bilateral soma 2 weeks, distant bilaterally at 5.5 months post-injury. Impact pathologies co-localized serum albumin extravasation diagnostically detectable living dynamic contrast-enhanced MRI. These were also accompanied early, persistent, impairment axonal conduction velocity hippocampus defective long-term potentiation synaptic neurotransmission medial prefrontal cortex, regions acute injury. Surprisingly, deficits time did not correlate microgliosis, tauopathy, or electrophysiological dysfunction. Furthermore, observed but blast exposure under experimental conditions matched for kinematics. Computational modelling showed generated focal point loading seven-fold greater peak shear stress compared exposure. Moreover, intracerebral peaked before onset gross motion. By comparison, induced distributed force diffuse, lower magnitude brain. conclude mechanics shape responses, structural damage, neuropathological sequelae triggered neurotrauma. results indicate injuries, independent concussive signs, can as well early functional encephalopathy. shed light origins concussion relationship its aftermath.

Язык: Английский

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Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link

EBioMedicine, Год журнала: 2018, Номер 28, С. 21 - 30

Опубликована: Янв. 31, 2018

Traumatic brain injury (TBI) and Alzheimer's disease (AD) are devastating neurological disorders, whose complex relationship is not completely understood. Cerebrovascular pathology, a key element in both conditions, could represent mechanistic link between Aβ/tau deposition after TBI the development of post concussive syndrome, dementia chronic traumatic encephalopathy (CTE). In addition to debilitating acute effects, TBI-induced neurovascular injuries accelerate amyloid β (Aβ) production perivascular accumulation, arterial stiffness, tau hyperphosphorylation tau/Aβ-induced blood barrier damage, giving rise deleterious feed-forward loop. We postulate that can initiate cerebrovascular which causally involved multiple forms neurodegeneration including AD-like dementias. this review, we will explore how novel biomarkers, animal human studies with focus on dysfunction contributing understanding consequences pathology.

Язык: Английский

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Serum neurofilament light protein predicts clinical outcome in traumatic brain injury

Scientific Reports, Год журнала: 2016, Номер 6(1)

Опубликована: Ноя. 7, 2016

Abstract Axonal white matter injury is believed to be a major determinant of adverse outcomes following traumatic brain (TBI). We hypothesized that measurement neurofilament light protein (NF-L), found in long white-matter axons, blood samples, may serve as suitable biomarker for neuronal damage TBI patients. To test our hypotheses, we designed study two parts: i) developed an immunoassay based on Single molecule array technology quantification NF-L blood, and ii) proof-of-concept study, tested newly method serial serum samples from severe (sTBI) patients (n = 72) controls 35). also compared the diagnostic prognostic utility with established S100B. levels were markedly increased sTBI controls. at admission yielded AUC 0.99 detect versus (AUC 0.96 S100B), 1.00 day 12 (0.65 S100B). Importantly, initial predicted poor 12-month clinical outcome. In contrast, S100B was not related Taken together, data suggests useful assess severity sTBI.

Язык: Английский

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Traumatic brain injury and risk of dementia in older veterans

Neurology, Год журнала: 2014, Номер 83(4), С. 312 - 319

Опубликована: Июнь 26, 2014

Objectives:

Traumatic brain injury (TBI) is common in military personnel, and there growing concern about the long-term effects of TBI on brain; however, few studies have examined association between risk dementia veterans.

Methods:

We performed a retrospective cohort study 188,764 US veterans aged 55 years or older who had at least one inpatient outpatient visit during both baseline (2000–2003) follow-up (2003–2012) periods did not diagnosis baseline. diagnoses were determined using ICD-9 codes electronic medical records. Fine-Gray proportional hazards models used to determine whether was associated with greater incident dementia, accounting for competing death adjusting demographics, comorbidities, psychiatric disorders.

Results:

Veterans mean age 68 During 9-year period, 16% those developed compared 10% without (adjusted hazard ratio, 1.57; 95% confidence interval: 1.35–1.83). There evidence an additive other conditions dementia.

Conclusions:

60% increase developing over 9 after risks potential confounders. Our results suggest that may predispose toward development symptomatic raise consequences younger civilians.

Язык: Английский

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Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers

Nature Reviews Neurology, Год журнала: 2013, Номер 9(4), С. 192 - 200

Опубликована: Апрель 1, 2013

Язык: Английский

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Blast-related traumatic brain injury

The Lancet Neurology, Год журнала: 2013, Номер 12(9), С. 882 - 893

Опубликована: Июль 22, 2013

Язык: Английский

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Lost after translation: missorting of Tau protein and consequences for Alzheimer disease

Trends in Neurosciences, Год журнала: 2014, Номер 37(12), С. 721 - 732

Опубликована: Сен. 12, 2014

Язык: Английский

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Inflammation in epileptogenesis after traumatic brain injury

Journal of Neuroinflammation, Год журнала: 2017, Номер 14(1)

Опубликована: Янв. 13, 2017

Epilepsy is a common and debilitating consequence of traumatic brain injury (TBI). Seizures contribute to progressive neurodegeneration poor functional psychosocial outcomes for TBI survivors, epilepsy after often resistant existing anti-epileptic drugs. The development post-traumatic (PTE) occurs in complex neurobiological environment characterized by ongoing TBI-induced secondary processes. Neuroinflammation an important process, though how it contributes epileptogenesis, the chronic, spontaneous seizure activity, remains poorly understood. A mechanistic understanding inflammation (epileptogenesis) facilitate identification novel therapeutic strategies reduce or prevent seizures. We reviewed previous clinical pre-clinical data evaluate hypothesis that seizures TBI. Increasing evidence indicates neuroinflammation epileptic also epileptogenesis as well initiation (ictogenesis) perpetuation. Three key signaling factors implicated both activity pathogenesis are highlighted this review: high-mobility group box protein-1 interacting with toll-like receptors, interleukin-1β its transforming growth factor-β from extravascular albumin. Lastly, we consider age-dependent differences susceptibility mechanisms which may heightened vulnerability young brain-injured patients. Several inflammatory mediators exhibit epileptogenic ictogenic properties, acting on glia neurons directly indirectly influence neuronal excitability. Further research required establish causality between cascades post-TBI, potential pharmaceuticals targeting pathways mitigate PTE.

Язык: Английский

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