The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model and Injury Paradigm Experience

Turner, Ryan C.; Lucke‐Wold, Brandon; Logsdon, Aric F.; Robson, Matthew J.; Dashnaw, Matthew L.; Huang, Jason H.; Smith, Kelley E; Huber, Jason D.; Rosen, Charles L.; Petraglia, Anthony L.

doi:10.3389/fneur.2015.00222

Cited by 30 publications

(27 citation statements)

References 48 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…130 A series of contributions from Petraglia et al [131][132][133][134] have described the pathological and behavioral effects of repetitive TBI in a closed skull model of TBI in mice and demonstrated the clearly greater effects of multiple impacts on a variety of behavioral measures. While much attention has been focused on the cellular (both neural and glial) response to TBI, as well as its behavioral consequences, less attention has been directed toward understanding possible effects of TBI on cerebral vasculature.…”

Section: Comparison Of Single Vs Multiple Impactsmentioning

confidence: 99%

Effects of concussion on the blood–brain barrier in humans and rodents

Sahyouni

Gutierrez

Gold

et al. 2017

Journal of Concussion

View full text Add to dashboard Cite

Traumatic brain injury and the long-term consequences of repeated concussions constitute mounting concerns in the United States, with 5.3 million individuals living with a traumatic brain injury-related disability. Attempts to understand mechanisms and possible therapeutic approaches to alleviate the consequences of repeat mild concussions or traumatic brain injury on cerebral vasculature depend on several aspects of the trauma, including: (1) the physical characteristics of trauma or insult that result in damage; (2) the time ''window'' after trauma in which neuropathological features develop; (3) methods to detect possible breakdown of the blood-brain barrier; and (4) understanding different consequences of a single concussion as compared with multiple concussions. We review the literature to summarize the current understanding of blood-brain barrier and endothelial cell changes post-neurotrauma in concussions and mild traumatic brain injury. Attention is focused on concussion and traumatic brain injury in humans, with a goal of pointing out the gaps in our knowledge and how studies of rodent model systems of concussion may help in filling these gaps. Specifically, we focus on disruptions that concussion causes to the blood-brain barrier and its multifaceted consequences. Importantly, the magnitude of post-concussion blood-brain barrier dysfunction may influence the time course and extent of neuronal recovery; hence, we include in this review comparisons of more severe traumatic brain injury to concussion where appropriate. Finally, we address the important, and still unresolved, issue of how best to detect possible breakdown in the blood-brain barrier following neurotrauma by exploring intravascular tracer injection in animal models to examine leakage into the brain parenchyma.

show abstract

Section: Comparison Of Single Vs Multiple Impactsmentioning

confidence: 99%

Effects of concussion on the blood–brain barrier in humans and rodents

Sahyouni

Gutierrez

Gold

et al. 2017

Journal of Concussion

View full text Add to dashboard Cite

show abstract

“…We found that ER stress is increased in cells that are undergoing apoptosis as well as those that develop tauopathy [25]. The key markers that were increased were markers of tau hyperphosphorylation AT100, PHF, and CP-13 [26]. It is apparent that tau hyperphosphorylation is an end-stage marker.…”

Section: Current Understanding Of Ctementioning

confidence: 81%

Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

et al. 2017

View full text Add to dashboard Cite

Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration.

show abstract

“…Similar to blast injury, increases in tau phosphorylation and pathologic tau conformations have been found one month following a single closed head injury (Turner et al , 2015). However, other studies have shown a requirement for repeat injuries in order to induce tau pathology following closed head injury.…”

Section: Tbi Tau and Cte - The Animal Modelsmentioning

confidence: 98%

Section: Tbi Tau and Cte - The Animal Modelsmentioning

confidence: 99%

“…Tau phosphorylation and pathologic tau conformations are increased in rat hippocampus and cortex one month following either a single blast or six blasts spaced 48h apart (Turner et al , 2015). Furthermore, rats exposed to repeat injury showed evidence of perivascular tau pathology, a defining feature of human CTE (Turner et al , 2015). Seventy days following a single blast injury in rats, total tau protein is also increased in several brain regions including the amygdala, prefrontal cortex and hippocampus; an affect which can be attenuated by environmental enrichment (Kovesdi et al , 2011).…”

Section: Tbi Tau and Cte - The Animal Modelsmentioning

confidence: 99%

See 1 more Smart Citation

Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology

Kulbe

Hall

2017

Progress in Neurobiology

View full text Add to dashboard Cite

In recent years, a new neurodegenerative tauopathy labeled Chronic Traumatic Encephalopathy (CTE), has been identified that is believed to be primarily a sequela of repeated mild traumatic brain injury (TBI), often referred to as concussion, that occurs in athletes participating in contact sports (e.g. boxing, football, football, rugby, soccer, ice hockey) or in military combatants, especially after blast-induced injuries. Since the identification of CTE, and its neuropathological finding of deposits of hyperphosphorylated tau protein, mechanistic attention has been on lumping the disorder together with various other non-traumatic neurodegenerative tauopathies. Indeed, brains from suspected CTE cases that have come to autopsy have been confirmed to have deposits of hyperphosphorylated tau in locations that make its anatomical distribution distinct for other tauopathies. The fact that these individuals experienced repetitive TBI episodes during their athletic or military careers suggests that the secondary injury mechanisms that have been extensively characterized in acute TBI preclinical models, and in TBI patients, including glutamate excitotoxicity, intracellular calcium overload, mitochondrial dysfunction, free radical-induced oxidative damage and neuroinflammation, may contribute to the brain damage associated with CTE. Thus, the current review begins with an in depth analysis of what is known about the tau protein and its functions and dysfunctions followed by a discussion of the major TBI secondary injury mechanisms, and how the latter have been shown to contribute to tau pathology. The value of this review is that it might lead to improved neuroprotective strategies for either prophylactically attenuating the development of CTE or slowing its progression.

show abstract

The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model and Injury Paradigm Experience

Cited by 30 publications

References 48 publications

Effects of concussion on the blood–brain barrier in humans and rodents

Effects of concussion on the blood–brain barrier in humans and rodents

Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology

Contact Info

Product

Resources

About