Chronic Traumatic Encephalopathy: The cellular sequela to repetitive brain injury

Vile, Alexander; Atkinson, Leigh

doi:10.1016/j.jocn.2017.03.035

Cited by 18 publications

(10 citation statements)

References 84 publications

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“…Interestingly, a calpain-generated fragment of brain spectrin, SNTF, has been reported to represent a blood biomarker for mild traumatic brain injury [54]. Furthermore, we also found that calpainmediated truncation of PTPN13, the calpain-2 PDZ binding partner, represents a new link between calpain-2 activation and tau phosphorylation, which is a hallmark of chronic traumatic encephalopathy [55]. This finding also supports the notion that a selective calpain-2 inhibitor could be beneficial for the prevention of brain damage resulting from repeated mild traumatic brain injury.…”

Section: Potential Therapeutic Applications Of a Selective Calpain-2 mentioning

confidence: 52%

Calpain-1 and Calpain-2 in the Brain: Dr. Jekill and Mr Hyde?

Baudry

2019

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While the calpain system has now been discovered for over 50 years, there is still a paucity of information regarding the organization and functions of the signaling pathways regulated by these proteases, although calpains play critical roles in many cell functions. Moreover, calpain overactivation has been shown to be involved in numerous diseases. Among the 15 calpain isoforms identified, calpain-1 (aka µ-calpain) and calpain-2 (aka m-calpain) are ubiquitously distributed in most tissues and organs, including the brain. We have recently proposed that calpain-1 and calpain- 2 play opposite functions in the brain, with calpain-1 activation being required for triggering synaptic plasticity and neuroprotection (Dr. Jekill), and calpain-2 limiting the extent of plasticity and being neurodegenerative (Mr. Hyde). Calpain-mediated cleavage has been observed in cytoskeleton proteins, membrane-associated proteins, receptors/channels, scaffolding/anchoring proteins, and protein kinases and phosphatases. This review will focus on the signaling pathways related to local protein synthesis, cytoskeleton regulation and neuronal survival/death regulated by calpain-1 and calpain-2, in an attempt to explain the origin of the opposite functions of these 2 calpain isoforms. This will be followed by a discussion of the potential therapeutic applications of selective regulators of these 2 calpain isoforms.

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Section: Potential Therapeutic Applications Of a Selective Calpain-2 mentioning

confidence: 52%

Calpain-1 and Calpain-2 in the Brain: Dr. Jekill and Mr Hyde?

Baudry

2019

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“…With the recognition that multiple head injuries, even of sub-threshold severity, are connected to chronic sequel, such as CTE (McKee et al, 2016; Vile and Atkinson, 2017), new models were developed to account for those findings. A growing number of studies in repeated injury rodent models (Shitaka et al, 2011; Klemenhagen et al, 2013; Mannix et al, 2014; Semple et al, 2016; Robinson et al, 2017) indicate that the glial response, in particular increases in microglia numbers and changes in morphology, shares an overall similar pattern with the traditional single-injury models.…”

Section: Microglial Activation In Animal Models Of Tbimentioning

confidence: 99%

Microglial Activation in Traumatic Brain Injury

Donat

Scott

Gentleman

et al. 2017

Front. Aging Neurosci.

343

279

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Microglia have a variety of functions in the brain, including synaptic pruning, CNS repair and mediating the immune response against peripheral infection. Microglia rapidly become activated in response to CNS damage. Depending on the nature of the stimulus, microglia can take a number of activation states, which correspond to altered microglia morphology, gene expression and function. It has been reported that early microglia activation following traumatic brain injury (TBI) may contribute to the restoration of homeostasis in the brain. On the other hand, if they remain chronically activated, such cells display a classically activated phenotype, releasing pro-inflammatory molecules, resulting in further tissue damage and contributing potentially to neurodegeneration. However, new evidence suggests that this classification is over-simplistic and the balance of activation states can vary at different points. In this article, we review the role of microglia in TBI, analyzing their distribution, morphology and functional phenotype over time in animal models and in humans. Animal studies have allowed genetic and pharmacological manipulations of microglia activation, in order to define their role. In addition, we describe investigations on the in vivo imaging of microglia using translocator protein (TSPO) PET and autoradiography, showing that microglial activation can occur in regions far remote from sites of focal injuries, in humans and animal models of TBI. Finally, we outline some novel potential therapeutic approaches that prime microglia/macrophages toward the beneficial restorative microglial phenotype after TBI.

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“…Approximately two decades later, Critchley [ 136 ] coined the term ‘chronic traumatic encephalopathy’ (CTE), which has been widely accepted by clinicians and scientists to explain persisting clinical symptoms and underlying degenerative changes after head trauma [ 137–140 ]. Today, the term CTE is mainly used to indicate a neurodegenerative disease in individuals who suffered repeated concussions and subsequently developed progressive dementia [ 141 , 142 ]. The main molecular mechanisms of CTE revolve around hyperphosphorylation of τ, which leads to its dissociation from tubulin and consequent dysfunction of microtubules.…”

Section: Clinical Manifestationsmentioning

confidence: 99%

Understanding blast-induced neurotrauma: how far have we come?

Černak

2017

Concussion

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Blast injuries, including blast-induced neurotrauma (BINT), are caused by blast waves generated during an explosion. Accordingly, their history coincides with that of explosives. Hence, it is intriguing that, after more than 1000 years of using explosives, our understanding of the pathological consequences of blast and body/brain interactions is extremely limited. Postconflict recovery mechanisms seemingly include the suppression of painful experiences, such as explosive injuries. Unfortunately, ignoring the knowledge generated by previous generations of scientists retards research progress, leading to superfluous and repetitive studies. This article summarizes clinical and experimental findings published about blast injuries and BINT following the wars of the 20th and 21th centuries. Moreover, it offers a personal view on potential factors interfering with the progress of BINT research working toward providing better diagnosis, treatment and rehabilitation for military personnel affected by blast exposure.

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Chronic Traumatic Encephalopathy: The cellular sequela to repetitive brain injury

Cited by 18 publications

References 84 publications

Calpain-1 and Calpain-2 in the Brain: Dr. Jekill and Mr Hyde?

Calpain-1 and Calpain-2 in the Brain: Dr. Jekill and Mr Hyde?

Microglial Activation in Traumatic Brain Injury

Understanding blast-induced neurotrauma: how far have we come?

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