| 1. |
- Bunketorp Käll, Lina, 1975, et al.
(författare)
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Long-Term Improvements After Multimodal Rehabilitation in Late Phase After Stroke A Randomized Controlled Trial
- 2017
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Ingår i: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 48:7, s. 1916-1924
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose-Treatments that improve function in late phase after stroke are urgently needed. We assessed whether multimodal interventions based on rhythm-and-music therapy or horse-riding therapy could lead to increased perceived recovery and functional improvement in a mixed population of individuals in late phase after stroke. Methods-Participants were assigned to rhythm-and-music therapy, horse-riding therapy, or control using concealed randomization, stratified with respect to sex and stroke laterality. Therapy was given twice a week for 12 weeks. The primary outcome was change in participants' perception of stroke recovery as assessed by the Stroke Impact Scale with an intention-to-treat analysis. Secondary objective outcome measures were changes in balance, gait, grip strength, and cognition. Blinded assessments were performed at baseline, postintervention, and at 3-and6-month follow-up. Results-One hundred twenty-three participants were assigned to rhythm-and-music therapy (n=41), horse-riding therapy (n=41), or control (n=41). Post-intervention, the perception of stroke recovery ( mean change from baseline on a scale ranging from 1 to 100) was higher among rhythm-and-music therapy (5.2 [95% confidence interval, 0.79-9.61]) and horse-riding therapy participants (9.8 [95% confidence interval, 6.00-13.66]), compared with controls (-0.5 [-3.20 to 2.28]); P=0.001 (1-way ANOVA). The improvements were sustained in both intervention groups 6 months later, and corresponding gains were observed for the secondary outcomes. Conclusions-Multimodal interventions can improve long-term perception of recovery, as well as balance, gait, grip strength, and working memory in a mixed population of individuals in late phase after stroke.
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| 2. |
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| 3. |
- Bunketorp Käll, Lina, 1975, et al.
(författare)
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The effects of a rhythm and music-based therapy program and therapeutic riding in late recovery phase following stroke: a study protocol for a three-armed randomized controlled trial.
- 2012
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Ingår i: BMC neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Stroke represents one of the most costly and long-term disabling conditions in adulthood worldwide and there is a need to determine the effectiveness of rehabilitation programs in the late phase after stroke. Limited scientific support exists for training incorporating rhythm and music as well as therapeutic riding and well-designed trials to determine the effectiveness of these treatment modalities are warranted. METHODS: A single blinded three-armed randomized controlled trial is described with the aim to evaluate whether it is possible to improve the overall health status and functioning of individuals in the late phase of stroke (1-5 years after stroke) through a rhythm and music-based therapy program or therapeutic riding. About 120 individuals will be consecutively and randomly allocated to one of three groups: (T1) A rhythm and music-based therapy program; (T2) therapeutic riding; or (T3) control group receiving the T1 training program a year later. Evaluation is conducted prior to and after the 12-week long intervention as well as three and six months later. The evaluation comprises a comprehensive functional and cognitive assessment (both qualitative and quantitative), and questionnaires. Based on the International classification of functioning, disability, and health (ICF), the outcome measures are classified into six comprehensive domains, with participation as the primary outcome measure assessed by the Stroke Impact Scale (SIS, version 2.0.). The secondary outcome measures are grouped within the following domains: body function, activity, environmental factors and personal factors. Life satisfaction and health related quality of life constitute an additional domain. Thus far, a total of 84 participants were randomised and have completed the intervention. Recruitment proceeds and follow-up is on-going, trial results are expected in 2014.Current statusA total of 84 participants were randomised and have completed the intervention. Recruitment proceeds and follow-up is on-going, trial results are expected in early 2014. DISCUSSION: This study will ascertain whether any of the two intervention programs can improve overall health status and functioning in the late phase of stroke. A positive outcome would increase the scientific basis for the use of such interventions in the late phase after stroke.Trial registrationClinical Trials.gov Identifier: NCT01372059.
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| 4. |
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| 5. |
- Pekny, Tulen, et al.
(författare)
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Short general anaesthesia induces prolonged changes in gene expression in the mouse hippocampus
- 2014
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172. ; 58:9, s. 1127-1133
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe long-term molecular changes in the central nervous system constitute an important aspect of general anaesthesia, but little is known about to what extent these molecular changes are affected by anaesthesia duration. The aim of the present study was to evaluate the effects of short duration (20min) general anaesthesia with isoflurane or avertin on the expression of 20 selected genes in the mouse hippocampus at 1 and 4 days after anaesthesia. MethodsNine to eleven-weeks-old male mice received one of the following treatments: 20min of avertin-induced anaesthesia (n=11), 20min of isoflurane-induced anaesthesia (n=10) and no anaesthesia (n=5). One and four days after anaesthesia, gene expression in the hippocampus was determined with reverse transcription quantitative real-time polymerase chain reaction. ResultsWe found that anaesthesia led to the upregulation of six genes: Hspd1 (heat shock protein 1), Plat (tissue plasminogen activator) and Npr3 (natriuretic peptide receptor 3) were upregulated only 1 day after anaesthesia, whereas Thbs4 (thrombospondin 4) was upregulated only 4 days after anaesthesia. Syp (synaptophysin) and Mgst1 (microsomal glutathione S-transferase 1) were upregulated at both time points. Hspd1, Mgst1 and Syp expression was increased regardless of the anaesthetic used, Npr3 and Plat were increased only in mice exposed to avertin, and Thbs4 was upregulated only after isoflurane-induced anaesthesia. ConclusionsThis study shows that some of the effects of short general anaesthesia on gene expression in the mouse hippocampus persist for at least 4 days.
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| 6. |
- Pekny, Tulen, et al.
(författare)
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Synemin is expressed in reactive astrocytes and Rosenthal fibers in Alexander disease
- 2014
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Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica. - : Wiley. - 0903-4641 .- 1600-0463. ; 122:1, s. 76-80
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Tidskriftsartikel (refereegranskat)abstract
- Alexander disease (AxD) is a neurodegenerative disorder with prominent white matter degeneration and the presence of Rosenthal fibers containing aggregates of glial fibrillary acidic protein (GFAP), and small stress proteins HSP27 and αB-crystallin, and widespread reactive gliosis. AxD is caused by mutations in GFAP, the main astrocyte intermediate filament protein. We previously showed that intermediate filament protein synemin is upregulated in reactive astrocytes after neurotrauma. Here, we examined immunohistochemically the presence of synemin in reactive astrocytes and Rosenthal fibers in two patients with AxD. There was an abundance of GFAP-positive Rosenthal fibers and widespread reactive gliosis in the white matter and subpial regions. Many of the GFAP-positive reactive astrocytes were positive for synemin, and synemin was also present in Rosenthal fibers. We show that synemin is expressed in reactive astrocytes in AxD, and is also present in Rosenthal fibers. The potential role of synemin in AxD pathogenesis remains to be investigated. © 2013 APMIS Published by Blackwell Publishing Ltd.
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| 7. |
- Wilhelmsson, Ulrika, 1970, et al.
(författare)
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Astrocytes negatively regulate neurogenesis through the Jagged1-mediated notch pathway.
- 2012
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Ingår i: Stem cells (Dayton, Ohio). - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 30:10, s. 2320-9
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Tidskriftsartikel (refereegranskat)abstract
- Adult neurogenesis is regulated by a number of cellular players within the neurogenic niche. Astrocytes participate actively in brain development, regulation of the mature central nervous system (CNS), and brain plasticity. They are important regulators of the local environment in adult neurogenic niches through the secretion of diffusible morphogenic factors, such as Wnts. Astrocytes control the neurogenic niche also through membrane-associated factors, however, the identity of these factors and the mechanisms involved are largely unknown. In this study, we sought to determine the mechanisms underlying our earlier finding of increased neuronal differentiation of neural progenitor cells when cocultured with astrocytes lacking glial fibrillary acidic protein (GFAP) and vimentin (GFAP(-/-) Vim(-/-) ). We used primary astrocyte and neurosphere cocultures to demonstrate that astrocytes inhibit neuronal differentiation through a cell-cell contact. GFAP(-/-) Vim(-/-) astrocytes showed reduced endocytosis of Notch ligand Jagged1, reduced Notch signaling, and increased neuronal differentiation of neurosphere cultures. This effect of GFAP(-/-) Vim(-/-) astrocytes was abrogated in the presence of immobilized Jagged1 in a manner dependent on the activity of γ-secretase. Finally, we used GFAP(-/-) Vim(-/-) mice to show that in the absence of GFAP and vimentin, hippocampal neurogenesis under basal conditions as well as after injury is increased. We conclude that astrocytes negatively regulate neurogenesis through the Notch pathway, and endocytosis of Notch ligand Jagged1 in astrocytes and Notch signaling from astrocytes to neural stem/progenitor cells depends on the intermediate filament proteins GFAP and vimentin.
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| 8. |
- Wilhelmsson, Ulrika, 1970, et al.
(författare)
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Injury leads to the appearance of cells with characteristics of both microglia and astrocytes in mouse and human brain.
- 2017
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Ingår i: Cerebral cortex. - : Oxford University Press (OUP). - 1460-2199 .- 1047-3211. ; 27:6, s. 3360-3377
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Tidskriftsartikel (refereegranskat)abstract
- Microglia and astrocytes have been considered until now as cells with very distinct identities. Here, we assessed the heterogeneity within microglia/monocyte cell population in mouse hippocampus and determined their response to injury, by using single-cell gene expression profiling of cells isolated from uninjured and deafferented hippocampus. We found that in individual cells, microglial markers Cx3cr1, Aif1, Itgam, and Cd68 were co-expressed. Interestingly, injury led to the co-expression of the astrocyte marker Gfap in a subpopulation of Cx3cr1-expressing cells from both the injured and contralesional hippocampus. Cells co-expressing astrocyte and microglia markers were also detected in the in vitro LPS activation/injury model and in sections from human brain affected by stroke, Alzheimer's disease, and Lewy body dementia. Our findings indicate that injury and chronic neurodegeneration lead to the appearance of cells that share molecular characteristics of both microglia and astrocytes, 2 cell types with distinct embryologic origin and function.
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| 9. |
- Andersson, Daniel, 1979, et al.
(författare)
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Plasticity Response in the Contralesional Hemisphere after Subtle Neurotrauma: Gene Expression Profiling after Partial Deafferentation of the Hippocampus
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Neurotrauma or focal brain ischemia are known to trigger molecular and structural responses in the uninjured hemisphere. These responses may have implications for tissue repair processes as well as for the recovery of function. To determine whether the plasticity response in the uninjured hemisphere occurs even after a subtle trauma, we subjected mice to a partial unilateral deafferentation of the hippocampus induced by stereotactically performed entorhinal cortex lesion (ECL). The expression of selected genes was assessed by quantitative real-time PCR in the hippocampal tissue at the injured side and the contralesional side at day 4 and 14 after injury. We observed that expression of genes coding for synaptotagmin 1, ezrin, thrombospondin 4, and C1q proteins, that have all been implicated in the synapse formation, re-arrangement and plasticity, were upregulated both in the injured and the contralesional hippocampus, implying a plasticity response in the uninjured hemisphere. Several of the genes, the expression of which was altered in response to ECL, are known to be expressed in astrocytes. To test whether astrocyte activation plays a role in the observed plasticity response to ECL, we took advantage of mice deficient in two intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP) and vimentin (GFAP(-/-) Vim(-/-)) and exhibiting attenuated astrocyte activation and reactive gliosis. The absence of GFAP and vimentin reduced the ECL-induced upregulation of thrombospondin 4, indicating that this response to ECL depends on astrocyte activation and reactive gliosis. We conclude that even a very limited focal neurotrauma triggers a distinct response at the contralesional side, which at least to some extent depends on astrocyte activation.
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| 10. |
- Andersson, Karin, 1972, et al.
(författare)
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Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis.
- 2018
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 115:51
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is an inflammatory joint disease with a neurological component including depression, cognitive deficits, and pain, which substantially affect patients' quality of daily life. Insulin-like growth factor 1 receptor (IGF1R) signaling is one of the factors in RA pathogenesis as well as a known regulator of adult neurogenesis. The purpose of this study was to investigate the association between IGF1R signaling and the neurological symptoms in RA. In experimental RA, we demonstrated that arthritis induced enrichment of IBA1+ microglia in the hippocampus. This coincided with inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) and up-regulation of IGF1R in the pyramidal cell layer of the cornus ammoni and in the dentate gyrus, reproducing the molecular features of the IGF1/insulin resistance. The aberrant IGF1R signaling was associated with reduced hippocampal neurogenesis, smaller hippocampus, and increased immobility of RA mice. Inhibition of IGF1R in experimental RA led to a reduction of IRS1 inhibition and partial improvement of neurogenesis. Evaluation of physical functioning and brain imaging in RA patients revealed that enhanced functional disability is linked with smaller hippocampus volume and aberrant IGF1R/IRS1 signaling. These results point to abnormal IGF1R signaling in the brain as a mediator of neurological sequelae in RA and provide support for the potentially reversible nature of hippocampal changes.
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| 11. |
- Andreasson, K. I., et al.
(författare)
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Targeting innate immunity for neurodegenerative disorders of the central nervous system
- 2016
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; , s. 653-693
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Tidskriftsartikel (refereegranskat)abstract
- Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7–9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. (Figure presented.) Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7–9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. © 2016 International Society for Neurochemistry
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| 12. |
- Aswendt, M., et al.
(författare)
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Reactive astrocytes prevent maladaptive plasticity after ischemic stroke
- 2022
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082. ; 209
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Tidskriftsartikel (refereegranskat)abstract
- Restoration of functional connectivity is a major contributor to functional recovery after stroke. We investigated the role of reactive astrocytes in functional connectivity and recovery after photothrombotic stroke in mice with attenuated reactive gliosis (GFAP–/–Vim–/–). Infarct volume and longitudinal functional connectivity changes were determined by in vivo T2-weighted magnetic resonance imaging (MRI) and resting-state functional MRI. Sensorimotor function was assessed with behavioral tests, and glial and neural plasticity responses were quantified in the peri-infarct region. Four weeks after stroke, GFAP–/–Vim–/– mice showed impaired recovery of sensorimotor function and aberrant restoration of global neuronal connectivity. These mice also exhibited maladaptive plasticity responses, shown by higher number of lost and newly formed functional connections between primary and secondary targets of cortical stroke regions and increased peri-infarct expression of the axonal plasticity marker Gap43. We conclude that reactive astrocytes modulate recovery-promoting plasticity responses after ischemic stroke. © 2021
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| 13. |
- Berg, Alexander, et al.
(författare)
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Axonal Regeneration after Sciatic Nerve Lesion Is Delayed but Complete in GFAP- and Vimentin-Deficient Mice.
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Peripheral axotomy of motoneurons triggers Wallerian degeneration of injured axons distal to the lesion, followed by axon regeneration. Centrally, axotomy induces loss of synapses (synaptic stripping) from the surface of lesioned motoneurons in the spinal cord. At the lesion site, reactive Schwann cells provide trophic support and guidance for outgrowing axons. The mechanisms of synaptic stripping remain elusive, but reactive astrocytes and microglia appear to be important in this process. We studied axonal regeneration and synaptic stripping of motoneurons after a sciatic nerve lesion in mice lacking the intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP) and vimentin, which are upregulated in reactive astrocytes and Schwann cells. Seven days after sciatic nerve transection, ultrastructural analysis of synaptic density on the somata of injured motoneurons revealed more remaining boutons covering injured somata in GFAP(-/-)Vim(-/-) mice. After sciatic nerve crush in GFAP(-/-)Vim(-/-) mice, the fraction of reinnervated motor endplates on muscle fibers of the gastrocnemius muscle was reduced 13 days after the injury, and axonal regeneration and functional recovery were delayed but complete. Thus, the absence of GFAP and vimentin in glial cells does not seem to affect the outcome after peripheral motoneuron injury but may have an important effect on the response dynamics.
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| 14. |
- Berg, A., et al.
(författare)
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Reduced removal of synaptic terminals from axotomized spinal motoneurons in the absence of complement C3
- 2012
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 237:1, s. 8-17
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Tidskriftsartikel (refereegranskat)abstract
- Complement proteins C1q and C3 play a critical role in synaptic elimination during development. Axotomy of spinal motoneurons triggers removal of synaptic terminals from the cell surface of motoneurons by largely unknown mechanisms. We therefore hypothesized that the complement system is involved also in synaptic stripping of injured motoneurons. In the sciatic motor pool of wild type (WT) mice, the immunoreactivity (IR) for both C1q and C3 was increased after sciatic nerve transection (SNT). Mice deficient in C3 (C3(-/-)) showed a reduced loss of synaptic terminals from injured motoneurons at one week after SNT, as assessed by immunoreactivity for synaptic markers and electron microscopy. In particular, the removal of putative inhibitory terminals, immunopositive for vesicular inhibitory amino acid transporter (VIAAT) and ultrastructurally identified as type F synapses, was reduced in C3(-/-) mice. In contrast, lesion-induced removal of nerve terminals in C1q(-/-) mice appeared similar to WT mice. Growth associated protein (GAP)-43 mRNA expression in lesioned motoneurons increased much more in C3(-/-) compared to WT mice after SNT. After sciatic nerve crush (SNC), the C3(-/-) mice showed a faster functional recovery, assessed as grip strength, compared to WT mice. No differences were detected regarding nerve inflammation at the site of injury or pattern of muscle reinnervation. These data indicate that a non-classical pathway of complement activation is involved in axotomy-induced adult synapse removal, and that its inhibition promotes functional recovery. (c) 2012 Elsevier Inc. All rights reserved.
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| 15. |
- Bunketorp Käll, Lina, 1975, et al.
(författare)
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Effects of horse-riding therapy and rhythm and music-based therapy on functional mobility in late phase after stroke
- 2019
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Ingår i: Neurorehabilitation. - : IOS Press. - 1053-8135 .- 1878-6448. ; 45:4, s. 483-492
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Persons with stroke commonly have residual neurological deficits that seriously OBJECTIVE: To investigate whether horse-riding therapy (H-RT) and rhythm and music-based therapy METHODS: This study is part of a randomized controlled trial in which H-RT and R-MT was provided RESULTS: 123 participants were assigned to H-RT (n = 41), R-MT (n = 41), or control (n = 41). Post- CONCLUSIONS: The present study supports the efficacy of H-RT in producing immediate gains in gait
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| 16. |
- Bunketorp Käll, Lina, 1975, et al.
(författare)
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Motor Function in the Late Phase After Stroke: Stroke Survivors' Perspective
- 2020
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Ingår i: Annals of Rehabilitation Medicine-Arm. - : Korean Academy of Rehabilitation Medicine. - 2234-0645 .- 2234-0653. ; 44:5, s. 362-369
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Tidskriftsartikel (refereegranskat)abstract
- Objective To examine the association between observer-assessed functional status and perceived recovery in the late phase after stroke. The study also aimed to determine whether observer-assessed functional improvements as a result of horse-riding therapy (H-RT) are related to enhanced perception of stroke recovery. Methods This is a descriptive correlational study using data derived from a three-armed randomized controlled trial in which 123 individuals were enrolled, among whom 43 received H-RT for 12 weeks. The measures included the Modified Motor Assessment Scale, Berg Balance Scale, Timed Up and Go, timed 10-m walk, and perceived recovery from stroke indicated by item #9 in the Stroke Impact Scale (version 2.0). Spearman rank order correlation (r(s)) was used in the analyses. Results There were moderate to strong positive or negative correlations between all four observer-assessed motor variables and participants' ratings of perceived late-phase stroke recovery at trial entrance, ranging from r(s)=-0.49 to r(s)=0.54 (p<0.001). The results of the correlational analyses of variable changes showed that, after the end of the H-RT intervention, both self-selected and fast gait speed improvement were significantly correlated with increments in self-rated stroke recovery (4=-0.41, p=0.01 and r(s)=-0.38, p=0.02, respectively). Conclusion This study provided data supporting the association between individual ratings of self-perceived recovery after stroke and observer-assessed individual motor function. The results further demonstrate that enhancement in perceived stroke recovery after completing the intervention was associated with objectively measured gains in both self-selected and fast gait speed.
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| 17. |
- Calkins, D. J., et al.
(författare)
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The challenge of regenerative therapies for the optic nerve in glaucoma
- 2017
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Ingår i: Experimental Eye Research. - : Elsevier BV. - 0014-4835. ; 157, s. 28-33
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Tidskriftsartikel (refereegranskat)abstract
- This review arose from a discussion of regenerative therapies to treat optic nerve degeneration in glaucoma at the 2015 Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration. In addition to the authors, participants included Jonathan Crowston, Andrew Huberman, Elaine Johnson, Richard Lu, Hemai Phatnami, Rebecca Sappington, and Don Zack. Glaucoma is a neurodegenerative disease of the optic nerve, and is the leading cause of irreversible blindness worldwide. The disease progresses as sensitivity to intraocular pressure (IOP) is conveyed through the optic nerve head to distal retinal ganglion cell (RGC) projections. Because the nerve and retina are components of the central nervous system (CNS), their intrinsic regenerative capacity is limited. However, recent research in regenerative therapies has resulted in multiple breakthroughs that may unlock the optic nerve's regenerative potential. Increasing levels of Schwann-cell derived trophic factors and reducing potent cell-intrinsic suppressors of regeneration have resulted in axonal regeneration even beyond the optic chiasm. Despite this success, many challenges remain. RGC axons must be able to form new connections with their appropriate targets in central brain regions and these connections must be retinotopically correct. Furthermore, for new axons penetrating the optic projection, oligodendrocyte glia must provide myelination. Additionally, reactive gliosis and inflammation that increase the regenerative capacity must be outweigh pro-apoptotic processes to create an environment within which maximal regeneration can occur. (C) 2017 Elsevier Ltd. All rights reserved.
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| 18. |
- Chen, Meng, et al.
(författare)
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Increased Neuronal Differentiation of Neural Progenitor Cells Derived from Phosphovimentin-Deficient Mice.
- 2018
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Ingår i: Molecular neurobiology. - : Springer Science and Business Media LLC. - 1559-1182 .- 0893-7648. ; 55:7, s. 5478-5489
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Tidskriftsartikel (refereegranskat)abstract
- Vimentin is an intermediate filament (also known as nanofilament) protein expressed in several cell types of the central nervous system, including astrocytes and neural stem/progenitor cells. Mutation of the vimentin serine sites that are phosphorylated during mitosis (VIMSA/SA) leads to cytokinetic failures in fibroblasts and lens epithelial cells, resulting in chromosomal instability and increased expression of cell senescence markers. In this study, we investigated morphology, proliferative capacity, and motility of VIMSA/SAastrocytes, and their effect on the differentiation of neural stem/progenitor cells. VIMSA/SAastrocytes expressed less vimentin and more GFAP but showed a well-developed intermediate filament network, exhibited normal cell morphology, proliferation, and motility in an in vitro wound closing assay. Interestingly, we found a two- to fourfold increased neuronal differentiation of VIMSA/SAneurosphere cells, both in a standard 2D and in Bioactive3D cell culture systems, and determined that this effect was neurosphere cell autonomous and not dependent on cocultured astrocytes. Using BrdU in vivo labeling to assess neural stem/progenitor cell proliferation and differentiation in the hippocampus of adult mice, one of the two major adult neurogenic regions, we found a modest increase (by 8%) in the fraction of newly born and surviving neurons. Thus, mutation of the serine sites phosphorylated in vimentin during mitosis alters intermediate filament protein expression but has no effect on astrocyte morphology or proliferation, and leads to increased neuronal differentiation of neural progenitor cells.
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| 19. |
- Chen, Meng, et al.
(författare)
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Neural Progenitor Cells in Cerebral Cortex of Epilepsy Patients do not Originate from Astrocytes Expressing GLAST.
- 2017
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Ingår i: Cerebral cortex (New York, N.Y. : 1991). - : Oxford University Press (OUP). - 1460-2199 .- 1047-3211. ; 27:12, s. 5672-5682
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Tidskriftsartikel (refereegranskat)abstract
- Adult neurogenesis in human brain is known to occur in the hippocampus, the subventricular zone, and the striatum. Neural progenitor cells (NPCs) were reported in the cortex of epilepsy patients; however, their identity is not known. Since astrocytes were proposed as the source of neural progenitors in both healthy and diseased brain, we tested the hypothesis that NPCs in the epileptic cortex originate from reactive, alternatively, de-differentiated astrocytes that express glutamate aspartate transporter (GLAST). We assessed the capacity to form neurospheres and the differentiation potential of cells dissociated from fresh cortical tissue from patients who underwent surgical treatment for pharmacologically intractable epilepsy. Neurospheres were generated from 57% of cases (8/14). Upon differentiation, the neurosphere cells gave rise to neurons, oligodendrocytes, and astrocytes. Sorting of dissociated cells showed that only cells negative for GLAST formed neurospheres. In conclusion, we show that cells with neural stem cell properties are present in brain cortex of epilepsy patients, and that these cells are not GLAST-positive astrocytes.
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| 20. |
- Cho, Kin-Sang, et al.
(författare)
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Re-establishing the regenerative potential of central nervous system axons in postnatal mice.
- 2005
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Ingår i: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 118:Pt 5, s. 863-72
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Tidskriftsartikel (refereegranskat)abstract
- At a certain point in development, axons in the mammalian central nervous system lose their ability to regenerate after injury. Using the optic nerve model, we show that this growth failure coincides with two developmental events: the loss of Bcl-2 expression by neurons and the maturation of astrocytes. Before postnatal day 4, when astrocytes are immature, overexpression of Bcl-2 alone supported robust and rapid optic nerve regeneration over long distances, leading to innervation of brain targets by day 4 in mice. As astrocytes matured after postnatal day 4, axonal regeneration was inhibited in mice overexpressing Bcl-2. Concurrent induction of Bcl-2 and attenuation of reactive gliosis reversed the failure of CNS axonal re-elongation in postnatal mice and led to rapid axonal regeneration over long distances and reinnervation of the brain targets by a majority of severed optic nerve fibers up to 2 weeks of age. These results suggest that an early postnatal downregulation of Bcl-2 and post-traumatic reactive gliosis are two important elements of axon regenerative failure in the CNS.
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| 21. |
- de Pablo, Yolanda, et al.
(författare)
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Drugs targeting intermediate filaments can improve neurosupportive properties of astrocytes.
- 2018
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Ingår i: Brain Research Bulletin. - : Elsevier BV. - 0361-9230. ; 136, s. 130-138
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Tidskriftsartikel (refereegranskat)abstract
- In response to central nervous system (CNS) injury, astrocytes upregulate intermediate filament (nanofilament) proteins GFAP and vimentin. Whereas the intermediate filament upregulation in astrocytes is important for neuroprotection in the acute phase of injury, it might inhibit the regenerative processes later on. Thus, timely modulation of the astrocyte intermediate filaments was proposed as a strategy to promote brain repair. We used clomipramine, epoxomicin and withaferin A, drugs reported to decrease the expression of GFAP, and assessed their effect on neurosupportive properties and resilience of astrocytes to oxygen and glucose deprivation (OGD). Clomipramine decreased protein levels of GFAP, as well as vimentin and nestin, and did not affect astrocyte resilience to oxidative stress. Withaferin A sensitized astrocytes to OGD. Both clomipramine and epoxomicin promoted the attachment and survival of neurons co-cultured with astrocytes under standard culture conditions. Moreover, epoxomicin increased neurosupportive properties of astrocytes after OGD. Our data point to clomipramine and epoxomicin as potential candidates for astrocyte modulation to improve outcome after CNS injury.
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| 22. |
- de Pablo, Yolanda, et al.
(författare)
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Intermediate filaments are important for astrocyte response to oxidative stress induced by oxygen-glucose deprivation and reperfusion
- 2013
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Ingår i: Histochemistry and Cell Biology. - : Springer Science and Business Media LLC. - 0948-6143 .- 1432-119X. ; 140:1, s. 81-91
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Tidskriftsartikel (refereegranskat)abstract
- As a response to central nervous system injury, astrocytes become reactive. Two cellular hallmarks of reactive gliosis are hypertrophy of astrocyte processes and upregulation of intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP), vimentin, nestin, and synemin. Astrocytes in mice devoid of GFAP and vimentin (GFAP (-/-) Vim (-/-)) do not form cytoplasmic intermediate filaments. GFAP (-/-) Vim (-/-) mice develop larger infarcts after ischemic stroke (Li et al. in J Cereb Blood Flow Metab 28(3):468-481, 2008). Here, we attempted to analyze the underlying mechanisms using oxygen-glucose deprivation (OGD), an in vitro ischemia model, examining a potential link between astrocyte intermediate filaments and reactive oxygen species (ROS). We observed a reorganization of the intermediate filament network in astrocytes exposed to OGD. ROS accumulation was higher in GFAP (-/-) Vim (-/-) than wild-type astrocytes when exposed to OGD followed by reperfusion or when exposed to hydrogen peroxide. These results indicate that the elimination of ROS is impaired in the absence of the intermediate filament system. Compared to wild-type astrocytes, GFAP (-/-) Vim (-/-) astrocytes exposed to OGD and reperfusion exhibited increased cell death and conferred lower degree of protection to cocultured neurons. We conclude that the astrocyte intermediate filament system is important for the cell response to oxidative stress induced by OGD followed by reperfusion.
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| 23. |
- de Pablo, Yolanda, et al.
(författare)
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Vimentin Phosphorylation Is Required for Normal Cell Division of Immature Astrocytes
- 2019
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- Vimentin (VIM) is an intermediate filament (nanofilament) protein expressed in multiple cell types, including astrocytes. Mice with VIM mutations of serine sites phosphorylated during mitosis (VIMSA/SA) show cytokinetic failure in fibroblasts and lens epithelial cells, chromosomal instability, facilitated cell senescence, and increased neuronal differentiation of neural progenitor cells. Here we report that in vitro immature VIMSA/SA astrocytes exhibit cytokinetic failure and contain vimentin accumulations that co-localize with mitochondria. This phenotype is transient and disappears with VIMSA/SA astrocyte maturation and expression of glial fibrillary acidic protein (GFAP); it is also alleviated by the inhibition of cell proliferation. To test the hypothesis that GFAP compensates for the effect of VIMSA/SA in astrocytes, we crossed the VIMSA/SA and GFAP(-/-) mice. Surprisingly, the fraction of VIMSA/SA immature astrocytes with abundant vimentin accumulations was reduced when on GFAP(-/-) background. This indicates that the disappearance of vimentin accumulations and cytokinetic failure in mature astrocyte cultures are independent of GFAP expression. Both VIMSA/SA and VIM(SA/SA)GFAP(-/-) astrocytes showed normal mitochondrial membrane potential and vulnerability to H2O2, oxygen/glucose deprivation, and chemical ischemia. Thus, mutation of mitotic phosphorylation sites in vimentin triggers formation of vimentin accumulations and cytokinetic failure in immature astrocytes without altering their vulnerability to oxidative stress.
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| 24. |
- Escartin, C., et al.
(författare)
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Reactive astrocyte nomenclature, definitions, and future directions
- 2021
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 24, s. 312-325
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Tidskriftsartikel (refereegranskat)abstract
- Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions. Good-bad binary classifications fail to describe reactive astrocytes in CNS disorders. Here, 81 researchers reach consensus on widespread misconceptions and provide definitions and recommendations for future research on reactive astrocytes.
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| 25. |
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