Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

Lucke‐Wold, Brandon; Turner, Ryan C.; Logsdon, Aric F.; Nguyen, Linda; Bailes, Julian E.; Lee, John M.; Robson, Matthew J.; Omalu, Bennet; Huber, Jason D.; Rosen, Charles L.

doi:10.3171/2015.3.jns141802

Cited by 50 publications

(58 citation statements)

References 60 publications

(70 reference statements)

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“…Human paraffin embedded specimens were collected from The standardized method of staining with primary and secondary antibodies was performed as has previously been published [2]. CTE brains were co-stained with MC1, which was kindly gifted from Dr. Peter Davies.…”

Section: Methodsmentioning

confidence: 99%

“…Promising preclinical data pointed to the role of endoplasmic reticulum stress and oxidative stress in the pathophysiology of neurodegeneration following neurotrauma [2,24]. The exact mechanism by which this occurs however was not completely elucidated.…”

Section: Current Understanding Of Ctementioning

confidence: 99%

“…Our group and others have shown that looking earlier in the disease process may be more valuable in finding a treatment solution that can be clinically successful. Secondary injury mechanisms such as oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation play a more important role in disease onset than previously assumed [1][2][3][4]. These secondary injury mechanisms can be primed by genetic predisposition and triggered by insults such as neurotrauma, drug abuse, and cardiovascular disease [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Current Understanding Of Ctementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…Increases in ER stress are reported to occur in both single (Begum et al, 2014; Krajewska et al, 2011; Larner et al, 2004; Logsdon et al, 2014) and repetitive TBI (Lucke-Wold et al , 2016). In fact, calcium release from the ER has been hypothesized to be toxic to neurons and white matter tracts (Weber, 2012).…”

Section: Traumatic Brain Injury - Pathophysiological Mechanismsmentioning

confidence: 99%

“…ER stress has been documented in several tauopathies, including AD, FTD, and CTE, and correlates with tau hyperphosphorylation (Hoozemans and Scheper, 2012; Hoozemans et al , 2009; Lucke-Wold et al , 2016; Nijholt et al , 2012). ER dysfunction has been reported to occur both upstream and downstream of pathologic tau formation (Ho et al , 2012).…”

Section: The Role Of Tau In Cellular Dysfunctionmentioning

confidence: 99%

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

Kulbe

Hall

2017

Progress in Neurobiology

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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.

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Tetrandrine alleviates inflammation and neuron apoptosis in experimental traumatic brain injury by regulating the IRE1α/JNK/CHOP signal pathway

Liu

et al. 2022

Brain and Behavior

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Aim:The aim of this study was to investigate the therapeutic roles of Tetrandrine (TET) on traumatic brain injury (TBI) and the underlying mechanism. Method: Traumatic injury model of hippocampal neurons and TBI mouse model were established to evaluate the therapeutic effects. The expression of neuron-specific enolase (NSE), Caspase 3, and Caspase 12 was detected by immunofluorescence. The expression of TNF-α, NF-κB, TRAF1, ERS markers (GADD34 and p-PERK), IRE1α, CHOP, JNK, and p-JNK were evaluated by western blot. Flow cytometry was used to determine the apoptosis of neurons. Brain injury was assessed by Garcia score, cerebral water content, and Evan blue extravasation test. Hematoxylin and eosin staining was used to determine the morphological changes of hippocampal tissue. Apoptosis was assessed by TUNEL staining. Result: In traumatic injury model of hippocampal neurons, TET downregulated NSE, TNF-α, NF-κB, TRAF1, GADD34, p-PERK, IRE1α, CHOP, and p-JNK expression. TET reduced Caspase 3 and Caspase 12 cleavage. Apoptosis rate was inhibited by the introduction of TET. TET improved the Garcia neural score, decreased the cerebral water content and Evans blue extravasation, and reduced NSE, TNF-α, NF-κB, TRAF1, IRE1α, CHOP, and p-JNK expression in mice with TBI, which was significantly reversed by Anisomycin, a JNK selective activator. Conclusion: TET alleviated inflammation and neuron apoptosis in experimental TBI by regulating the IRE1α/JNK/CHOP signal pathway.

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Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

Cited by 50 publications

References 60 publications

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

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

Tetrandrine alleviates inflammation and neuron apoptosis in experimental traumatic brain injury by regulating the IRE1α/JNK/CHOP signal pathway

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