Recent Preclinical Insights Into the Treatment of Chronic Traumatic Encephalopathy

Breen, Patrick; Krishnan, Vaishnav

doi:10.3389/fnins.2020.00616

Cited by 15 publications

(14 citation statements)

References 81 publications

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“…We found activation of the mTOR pathway and the inflammasome, as well as upregulation of a Tau kinase and accumulation of hyperphosphorylated, misfolded Tau, 14 months after injury (approximating 47 years in humans) (Flurkey et al, 2007). Hyperphosphorylated tau is associated with neurofibrillary tangles in AD and CTE, and inhibition of tau kinases, such as GSK3b and CDK5, has been a top research strategy to inhibit pathologic tau accumulation and prevent neurodegenerative diseases (Breen and Krishnan, 2020). Notably, IL-1R1 À/À mice did not accumulate phospho-Tau in injured cerebellum.…”

Section: Discussionmentioning

confidence: 92%

Repetitive Mild Closed Head Injury in Adolescent Mice Is Associated with Impaired Proteostasis, Neuroinflammation, and Tauopathy

Kalish

Finander

et al. 2022

J. Neurosci.

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Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurologic sequelae and is linked to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury model that induces progressive cognitive impairment in males and anxiety in females in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single-nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis and evidence for disrupted ligand-receptor signaling networks in injured mice. Western blot analysis of isolated neurons showed evidence of inflammasome activation and downstream IL-1b processing, as previously demonstrated in acute CNS injury models, and accumulation of misfolded, hyperphosphorylated tau, and changes in expression of proteins suggestive of impaired translation in males but not in females. At 6 months, injured IL-1 receptor 1 (IL-1R1) KO mice, which are protected from postinjury cognitive deficits, had decreased accumulation of pro-IL-1b and misfolded tau in cortex and cerebellum, suggesting that IL-1R1 is upstream of inflammasome priming (defined as increase in pro-IL-1b) and abnormal tau phosphorylation. Together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurologic dysfunction and neurodegeneration.

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Section: Discussionmentioning

confidence: 92%

Repetitive Mild Closed Head Injury in Adolescent Mice Is Associated with Impaired Proteostasis, Neuroinflammation, and Tauopathy

Kalish

Finander

et al. 2022

J. Neurosci.

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“…However, the preclinical understanding and development of CTE therapies remains limited by our abilities to model this disease preclinically. While some TBI models have shown acute increases in phosphorylated Tau, limited studies have demonstrated Tau inclusions and other CTE-like pathologies 80 . In most studies, researchers have relied on overexpression of human isoforms of Tau and demonstrating an increased potential to aggregate following head trauma 80 .…”

Section: Discussionmentioning

confidence: 99%

“…While some TBI models have shown acute increases in phosphorylated Tau, limited studies have demonstrated Tau inclusions and other CTE-like pathologies 80 . In most studies, researchers have relied on overexpression of human isoforms of Tau and demonstrating an increased potential to aggregate following head trauma 80 . While our finding here is exciting, more work will need to be conducted to determine the chronic effects of rTBI and the corresponding CTE-like pathologies including: the degree of TDP-43 pathology, stereological assessments of depleted neuronal populations, and solubility/isotypes of Tau inclusions.…”

Section: Discussionmentioning

confidence: 99%

Cdk5 mediates rotational force-induced brain injury

Umfress

Chakraborti

Devi

et al. 2023

Sci Rep

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Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks, months, and lifetime after injury. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of repetitive rotational head trauma in rodents and demonstrated acute and prolonged pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant Cyclin-dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI. We utilized Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.

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“…These treatments are hypothesised to have disease-modifying effects by reducing the concentrations of toxic forms of tau in the brain or by compensating for the loss of tau function. 40 Also a series of candidate treatments, including kinase inhibitors, antibody therapy and antiinflammatory drugs are evaluated in preclinical animal models of CTE. 41 However there are some dough's that the pathogenesis of CTE is correlated solely to the repeated concussive injuries alone.…”

Section: Discussionmentioning

confidence: 99%

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2021

JNSK

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Chronic traumatic encephalopathy is a progressive neurodegenerative disease occurring in retired sportspersons who have received several head blows with concussions during their games. The clinical symptoms start with mood disorders and with a progressive evolution into dementia and Parkinsonism. The disease is due to a progressive accumulation of hyperphosphorilated tau in neurons as neurofibrillary tangles, abnormal neurites and inclusions in astrocytes around small vessels. There is a tendency of the lesions to occur in clusters at the sulcal depths of the cerebral cortex. Chronic traumatic encephalopathy has to be differentiated from Alzheimer's disease, in which head trauma can also increase the illness symptoms. Recently, new tracers in positron emission topography of the brain have been used for a better evaluation of chronic traumatic encephalopathy. There is actually no treatment that allows to cure or to slowdown the evolution of chronic traumatic encephalopathy. However, new treatment studies are recently conducted and in progress.

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Recent Preclinical Insights Into the Treatment of Chronic Traumatic Encephalopathy

Cited by 15 publications

References 81 publications

Repetitive Mild Closed Head Injury in Adolescent Mice Is Associated with Impaired Proteostasis, Neuroinflammation, and Tauopathy

Repetitive Mild Closed Head Injury in Adolescent Mice Is Associated with Impaired Proteostasis, Neuroinflammation, and Tauopathy

Cdk5 mediates rotational force-induced brain injury

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