Beading of the astrocytic processes (clasmatodendrosis) following head trauma is associated with protein degradation pathways

Sakai, Kentaro; Fukuda, Takahiro; Iwadate, Kimiharu

doi:10.3109/02699052.2013.837198

Cited by 28 publications

(25 citation statements)

References 28 publications

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“…Given the exacerbated responses of both of these measures, they may lend themselves particularly well as prognostic indicators for aged individuals acutely after TBI [60] Our present findings demonstrating an age-related increase in clasmatodendrosis are corroborated by previous work examining human brain [43]. We observed the aggregation of this morphologically distinct subset of astrocytes confined to the stratum radiatum of the CA1, which recapitulates previous work in rodents demonstrating this as a susceptible region for accumulating these astrogliopathies [61][62][63]. Although the exact role or cause of this pathology is not well-defined, recent reports have demonstrated corollaries with senescence, autophagy, metabolic dysfunction, ER stress, and NFkB signaling [61,62,64,65].…”

Section: Discussionsupporting

confidence: 89%

“…We observed the aggregation of this morphologically distinct subset of astrocytes confined to the stratum radiatum of the CA1, which recapitulates previous work in rodents demonstrating this as a susceptible region for accumulating these astrogliopathies [61][62][63]. Although the exact role or cause of this pathology is not well-defined, recent reports have demonstrated corollaries with senescence, autophagy, metabolic dysfunction, ER stress, and NFkB signaling [61,62,64,65]. Moreover, our findings potentially highlight a trauma-induced turnover response occurring at the 3 day post-injury interval, such that the age-related accumulation of these degenerative astrocytes may be susceptible to inflammatory-mediated removal or clearance mechanisms, which remains to be elucidated.…”

Section: Discussionsupporting

confidence: 88%

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Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice

Early

Gorman

Eldik

et al. 2019

Preprint

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AbstractBackgroundOlder-age individuals are at the highest risk for disability from a traumatic brain injury (TBI). Astrocytes are the most numerous glia in the brain, necessary for brain function, yet there is little known about unique responses of astrocytes in the aged-brain following TBI.MethodsOur approach examined astrocytes in young adult, 4-month-old, versus aged, 18-month-old mice, at 1, 3, and 7 days post-TBI. We selected these time points to span the critical period in the transition from acute injury to presumably irreversible tissue damage and disability. Two approaches were used to define the astrocyte contribution to TBI by age interaction: 1) tissue histology and morphological phenotyping, and 2) transcriptomics on enriched astrocytes from the injured brain.ResultsAging was found to have a profound effect on the TBI-induced loss of homeostatic astrocyte function needed for maintaining water transport and edema – namely, aquaporin-4. The loss of homoeostatic responses was coupled with a progressive exacerbation of astrogliosis in the aged brain as a function of time after injury. Moreover, clasmatodendrosis, an underrecognized astrogliopathy, was found to be significantly increased in the aged brain, but not in the young brain. As a function of TBI, we observed a transitory refraction in the number of these astrocytes, which rebounded by 7 days post-injury in the aged brain. The transcriptomics found disproportionate changes in genes attributed to reactive astrocytes, inflammatory response, complement pathway, and synaptic support in aged mice following TBI compared to young mice. Additionally, our data highlight that TBI did not evoke a clear alignment with previously defined “A1/A2” dichotomy of reactive astrogliosis.ConclusionsOverall, our findings point toward a progressive phenotype of aged astrocytes following TBI that we hypothesize to be maladaptive, shedding new insights into potentially modifiable astrocyte-specific mechanisms that may underlie increased fragility of the aged brain to trauma.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 88%

Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice

Early

Gorman

Eldik

et al. 2019

Preprint

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“…Higher strain rates concurrent with blast exposure have been shown to induce blebbing in a subset of neurons due to strain stiffening of the cytoskeletal proteins [60]. Whether blast-induced-high-strain- rates or energy failure and acidosis previously reasoned as causal factors for clasmatodendrosis [59], accounted for observations in this study is not clear.…”

Section: Discussionmentioning

confidence: 90%

“…This irreversible degenerative morphology of astrocytes has been observed in brain samples linked to various disease states [Alzheimer’s disease in conjunction with cerebrovascular disorder [57]; epilepsy [43, 58]]. This astrocyte pathology has not been previously associated with blast induced neurotrauma, but clasmatodendritic astrocytes were present in human cerebral cortices as early as 1 hr after non-blast-induced traumatic brain injury [59]. Higher strain rates concurrent with blast exposure have been shown to induce blebbing in a subset of neurons due to strain stiffening of the cytoskeletal proteins [60].…”

Section: Discussionmentioning

confidence: 97%

Simulated blast overpressure induces specific astrocyte injury in an ex vivo brain slice model

et al. 2017

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Exposure to explosive blasts can produce functional debilitation in the absence of brain pathology detectable at the scale of current diagnostic imaging. Transient (ms) overpressure components of the primary blast wave are considered to be potentially damaging to the brain. Astrocytes participate in neuronal metabolic maintenance, blood–brain barrier, regulation of homeostatic environment, and tissue remodeling. Damage to astrocytes via direct physical forces has the potential to disrupt local and global functioning of neuronal tissue. Using an ex vivo brain slice model, we tested the hypothesis that viable astrocytes within the slice could be injured simply by transit of a single blast wave consisting of overpressure alone. A polymer split Hopkinson pressure bar (PSHPB) system was adapted to impart a single positive pressure transient with a comparable magnitude to those that might be present inside the head. A custom built test chamber housing the brain tissue slice incorporated revised design elements to reduce fluid space and promote transit of a uniform planar waveform. Confocal microscopy, stereology, and morphometry of glial fibrillary acidic protein (GFAP) immunoreactivity revealed that two distinct astrocyte injury profiles were identified across a 4 hr post-test survival interval: (a) presumed conventional astrogliosis characterized by enhanced GFAP immunofluorescence intensity without significant change in tissue area fraction and (b) a process comparable to clasmatodendrosis, an autophagic degradation of distal processes that has not been previously associated with blast induced neurotrauma. Analysis of astrocyte branching revealed early, sustained, and progressive differences distinct from the effects of slice incubation absent overpressure testing. Astrocyte vulnerability to overpressure transients indicates a potential for significant involvement in brain blast pathology and emergent dysfunction. The testing platform can isolate overpressure injury phenomena to provide novel insight on physical and biological mechanisms.

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“…Trauma-induced morphological changes of astrocytes, such as swelling and ultrastructural alterations, were previously perceived in an in vitro model of fluid percussion injury [149, 150], stretched-injured astrocytes [151], a rat bTBI model [152], and in patients with cerebral contusions [77, 153]. Likewise, clasmatodendrosis of astrocytes was detected in TBI patients from 1 h up to 14 days post injury [154]. Clasmatodendrosis in astrocytes was linked with the autophagic cell death [155, 156], suggesting autophagy as an additional mechanism of astrocytic death in OHCs at 2 h following blast exposure.…”

Section: Discussionmentioning

confidence: 99%

Acute death of astrocytes in blast-exposed rat organotypic hippocampal slice cultures

et al. 2017

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Blast traumatic brain injury (bTBI) affects civilians, soldiers, and veterans worldwide and presents significant health concerns. The mechanisms of neurodegeneration following bTBI remain elusive and current therapies are largely ineffective. It is important to better characterize blast-evoked cellular changes and underlying mechanisms in order to develop more effective therapies. In the present study, our group utilized rat organotypic hippocampal slice cultures (OHCs) as an in vitro system to model bTBI. OHCs were exposed to either 138 ± 22 kPa (low) or 273 ± 23 kPa (high) overpressures using an open-ended helium-driven shock tube, or were assigned to sham control group. At 2 hours (h) following injury, we have characterized the astrocytic response to a blast overpressure. Immunostaining against the astrocytic marker glial fibrillary acidic protein (GFAP) revealed acute shearing and morphological changes in astrocytes, including clasmatodendrosis. Moreover, overlap of GFAP immunostaining and propidium iodide (PI) indicated astrocytic death. Quantification of the number of dead astrocytes per counting area in the hippocampal cornu Ammonis 1 region (CA1), demonstrated a significant increase in dead astrocytes in the low- and high-blast, compared to sham control OHCs. However only a small number of GFAP-expressing astrocytes were co-labeled with the apoptotic marker Annexin V, suggesting necrosis as the primary type of cell death in the acute phase following blast exposure. Moreover, western blot analyses revealed calpain mediated breakdown of GFAP. The dextran exclusion additionally indicated membrane disruption as a potential mechanism of acute astrocytic death. Furthermore, although blast exposure did not evoke significant changes in glutamate transporter 1 (GLT-1) expression, loss of GLT-1-expressing astrocytes suggests dysregulation of glutamate uptake following injury. Our data illustrate the profound effect of blast overpressure on astrocytes in OHCs at 2 h following injury and suggest increased calpain activity and membrane disruption as potential underlying mechanisms.

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Beading of the astrocytic processes (clasmatodendrosis) following head trauma is associated with protein degradation pathways

Abstract: Clasmatodendrosis is associated with UPS-mediated, autophagy and relatively acute pathological findings after traumatic intracranial injury.

Cited by 28 publications

References 28 publications

Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice

Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice

Simulated blast overpressure induces specific astrocyte injury in an ex vivo brain slice model

Acute death of astrocytes in blast-exposed rat organotypic hippocampal slice cultures

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