| 1. |
- Olsson, Sandra, 1976, et al.
(författare)
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Genetic variation in complement component C3 shows association with ischaemic stroke.
- 2011
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Ingår i: European journal of neurology : the official journal of the European Federation of Neurological Societies. - : Wiley. - 1468-1331. ; 42, s. 214-16
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: The aim of this study was to investigate whether genetic variation at the third complement component (C3) locus is associated with ischaemic stroke (IS). Methods: The Sahlgrenska Academy Study on Ischaemic Stroke comprises 844 patients with IS, and 668 healthy controls. Sixteen SNPs were analyzed. Results: Two SNPs, rs2277984 and rs3745565, showed a significant association with overall IS. The SNP rs2277984 also showed association with the IS subtype cryptogenic stroke. These associations were independent of hypertension, diabetes, and smoking. The independent association between rs3745565 and overall IS withstands correction for multiple testing. Conclusion: In this sample of patients with IS, genetic variation in C3 is associated with IS.
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| 2. |
- Stokowska, Anna, et al.
(författare)
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Cardioembolic and Small Vessel Disease Stroke Show Differences in Associations between Systemic C3 Levels and Outcome
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Activation of the complement system has been proposed to play a role in the pathophysiology of stroke. As the specific involvement of the complement proteins may be influenced by stroke etiology, we compared plasma C3 and C3a levels in patients with cardioembolic (CE) and small vessel disease (SVD) subtypes of ischemic stroke and control subjects and evaluated their association to outcome at three months and two years. Methodology/Principal Findings: Plasma C3 and C3a levels in 79 CE and 79 SVD stroke patients, sampled within 10 days and at three months after stroke, and age- and sex-matched control subjects from The Sahlgrenska Academy Study on Ischemic Stroke were measured by ELISA. Functional outcome was assesed with modified Rankin Scale. In the CE group, plasma C3 levels were elevated only in the acute phase, whereas C3a was elevated at both time points. The follow-up phase plasma C3 levels in the upper third were associated with an increased risk of unfavorable outcome at three months (OR 7.12, CI 1.72-29.46, P = 0.007) as well as after two years (OR 8.25, CI 1.61-42.28, P = 0.011) after stroke. These associations withstand adjustment for age and sex. Conversely, three-month follow-up plasma C3a/C3 level ratios in the middle third were associated with favorable outcome after two years both in the univariate analysis (OR 0.19, CI 0.05-0.82, P = 0.026) and after adjustment for age and sex (OR 0.19, CI 0.04-0.88, P = 0.033). In the SVD group, plasma C3 and C3a levels were elevated at both time points but showed no significant associations with outcome. Conclusions: Plasma C3 and C3a levels are elevated after CE and SVD stroke but show associations with outcome only in CE stroke.
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| 3. |
- Stokowska, Anna, et al.
(författare)
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Plasma c3 and c3a levels in cryptogenic and large-vessel disease stroke: associations with outcome.
- 2011
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Ingår i: Cerebrovascular diseases (Basel, Switzerland). - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 32:2, s. 114-22
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Inflammation seems to be a key player in the pathophysiology of stroke. In this study, we compared plasma C3 and C3a levels in cryptogenic and large-vessel disease (LVD) subtypes of ischemic stroke and control subjects and evaluated their association to outcome at 3 months and 2 years. Methods: C3 and C3a levels in plasma of 79 cryptogenic stroke and 73 LVD stroke patients, sampled within 10 days and at 3 months after stroke, and age- and sex-matched control subjects from the Sahlgrenska Academy Study on Ischemic Stroke were measured by ELISA. Functional outcome was assessed with the modified Rankin Scale. Results: Plasma C3 was increased in both stroke groups at both time points. Systemic elevation of C3a was limited to the acute phase in the cryptogenic stroke group, whereas plasma C3a levels in the LVD group were also elevated at the 3-month follow-up. In the LVD group, plasma C3 levels in the upper third at the 3-month follow-up were associated with an unfavorable outcome after 3 months independently of age and sex: odds ratio (OR) 5.56; 95% confidence interval (CI) 1.03-29.93; p = 0.045; as well as after 2 years: OR 4.75; 95% CI 1.11-20.30; p = 0.036. In the cryptogenic stroke group, high plasma C3a levels in the acute phase were associated with an unfavorable outcome after 3 months: OR 3.75; 95% CI 1.01-13.96; p = 0.049 in univariate analysis but not after adjustment for age and sex (p = 0.050). Conclusions: Plasma C3 and C3a levels are elevated in cryptogenic and LVD stroke and the predictive value of these markers may depend on stroke subtype. Further studies on the role of the complement system in ischemic stroke outcome based on larger patient populations and controlling for the effect of infections, are clearly warranted.
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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- 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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| 9. |
- Bila, Custodio, et al.
(författare)
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Complement opsonization enhances friend virus infection of B cells and thereby amplifies the virus-specific CD8+ T cell response.
- 2011
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Ingår i: Journal of virology. - 1098-5514. ; 85:2, s. 1151-5
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Tidskriftsartikel (refereegranskat)abstract
- B cells are one of the targets of Friend virus (FV) infection, a well-established mouse model often used to study retroviral infections in vivo. Although B cells may be effective in stimulating cytotoxic T lymphocyte responses, studies involving their role in FV infection have mainly focused on neutralizing antibody production. Here we show that polyclonal activation of B cells promotes their infection with FV both in vitro and in vivo. Furthermore, we demonstrate that complement opsonization of Friend murine leukemia virus (F-MuLV) enhances infection of B cells, which correlates with increased potency of B cells to activate FV-specific CD8(+) T cells.
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| 10. |
- 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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| 11. |
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| 12. |
- 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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| 13. |
- 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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| 14. |
- 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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| 15. |
- Bykov, Igor, et al.
(författare)
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Complement C3 contributes to ethanol-induced liver steatosis in mice.
- 2006
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Ingår i: Annals of medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 38:4, s. 280-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: It is becoming increasingly clear that liver steatosis, a typical early consequence of alcohol exposure, sensitizes the liver to more severe inflammatory and fibrotic changes. On the other hand, activation of the key complement component C3, a central player in causing inflammation and tissue damage, is also known to be involved in the regulation of lipid metabolism. This prompted us to study the development of alcoholic liver steatosis in mice lacking C3 (C3-/-). RESULTS: Both C3-/- and normal C3+/+ mice were fed a steatosis-promoting high-fat diet with or without ethanol for 6 weeks. The diet without ethanol caused moderate liver steatosis in C3-/- but not in C3+/+ mice. As expected, ethanol-containing diet caused marked macrovesicular steatosis and increased the liver triglyceride content in C3+/+ mice. In contrast, ethanol diet tended to reduce steatosis and had no further effect on liver triglycerides in C3-/- mice. Furthermore, while in normal mice ethanol significantly increased the liver/body weight ratio, liver malondialdehyde level and serum alanine aminotransferase (ALT) activity, these effects were absent or small in C3-/- mice. A separate experiment with mice on chow diet confirmed the aberrant steatotic effect of ethanol in C3-/-mice: 4 hours after acute dosing of ethanol the liver triglyceride level had increased by 138% in C3+/+ mice (P<0.001), but only by 64% in C3-/- mice (n.s.). CONCLUSION. In C3-/- mice alcohol-induced liver steatosis is absent or strongly reduced after chronic or acute alcohol exposure. This suggests that the complement system and its component C3 contribute to the development of alcohol-induced fatty liver and its consequences.
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| 16. |
- Bykov, Igor, et al.
(författare)
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Effect of chronic ethanol consumption on the expression of complement components and acute-phase proteins in liver.
- 2007
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Ingår i: Clinical immunology (Orlando, Fla.). - : Elsevier BV. - 1521-6616. ; 124:2, s. 213-20
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Tidskriftsartikel (refereegranskat)abstract
- The complement system can provoke but also participate in the repair of liver injury. Here we investigated by microarray analysis the effect of chronic ethanol consumption on hepatic mRNA expression of complement components and acute-phase proteins in complement C3-deficient (C3(-/-)) and wild-type (C3(+/+)) mice. Up-regulation by ethanol of factor B, C1qA-chain and clusterin but down-regulation of factor H, Masp-2, factor D and the terminal components C6, C8alpha and C9 was seen in both strains. Ethanol up-regulated C2 and down-regulated C4bp only in C3(+/+) mice, while in C3(-/-) mice up-regulation of C1qB-chain and vitronectin was observed. The expression of factor B, C6, C1qB and factor I was lower but that of factor D higher in C3(-/-) than in C3(+/+) mice. Ethanol induced mRNA synthesis of many acute-phase proteins including SPARC and lipocalin-2, but reduced the expression of SAP. The induction of early classical and alternative pathway components and suppression of terminal pathway components and soluble regulators may thus contribute to alcohol-induced liver injury. Lipocalin-2 and SPARC emerge as new candidate markers for early detection of liver damage.
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| 17. |
- 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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| 18. |
- 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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| 19. |
- Chun, N., et al.
(författare)
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Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:6
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Tidskriftsartikel (refereegranskat)abstract
- The pathophysiology of myocardial injury that results from cardiac ischemia and reperfusion (I/R) is incompletely understood. Experimental evidence from murine models indicates that innate immune mechanisms including complement activation via the classical and lectin pathways are crucial. Whether factor B (f B), a component of the alternative complement pathway required for amplification of complement cascade activation, participates in the pathophysiology of myocardial I/R injury has not been addressed. We induced regional myocardial I/R injury by transient coronary ligation in WT C57BL/6 mice, a manipulation that resulted in marked myocardial necrosis associated with activation of fB protein and myocardial deposition of C3 activation products. In contrast, in f13(-/-) mice, the same procedure resulted in significantly reduced myocardial necrosis (% ventricular tissue necrotic; fB(-/-) mice, 20 4%; WT mice, 45 3%; P< 0.05) and diminished deposition of C3 activation products in the myocardial tissue (fB(-/-) mice, 0 0%; WT mice, 31 6%; P<0.05). Reconstitution of fB(-/-) mice with WT serum followed by cardiac I/R restored the myocardial necrosis and activated C3 deposition in the myocardium. In translational human studies we measured levels of activated fB (Bb) in intracoronary blood samples obtained during cardio-pulmonary bypass surgery before and after aortic cross clamping (AXCL), during which global heart ischemia was induced. Intracoronary Bb increased immediately after AXCL, and the levels were directly correlated with peripheral blood levels of cardiac troponin I, an established biomarker of myocardial necrosis (Spearman coefficient = 0.465, P < 0.01). Taken together, our results support the conclusion that circulating fB is a crucial pathophysiological
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| 20. |
- Daborg, Jonny, et al.
(författare)
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Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer's disease.
- 2012
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 1435-1463 .- 0300-9564. ; 119:7, s. 789-97
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is strongly associated with loss of synapses. The complement system has been shown to be involved in synaptic elimination. Several studies point to an association between AD and the complement system. The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls. Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers Aβ42, T-tau and P-tau. We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged. These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful.
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| 21. |
- Daborg, Jonny, et al.
(författare)
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Complement Gene Single Nucleotide Polymorphisms and Biomarker Endophenotypes of Alzheimer's Disease
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 35:1, s. 51-57
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Tidskriftsartikel (refereegranskat)abstract
- The complement system has been implicated in both physiological synapse elimination and Alzheimer's disease (AD). Here, we investigated associations between four single nucleotide polymorphisms (SNPs) in complement genes and cerebrospinal fluid (CSF) biomarkers for AD in 452 neurochemically or neuropathologically verified AD cases and 678 cognitively normal controls. None of the SNPs associated with risk of AD but there were potential associations of rs9332739 in the C2 gene and rs4151667 in the complement factor B gene with CSF tau levels (p = 0.023) and Mini-Mental State Examination scores (p = 0.012), both of which may be considered markers of disease intensity/severity.
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| 22. |
- 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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| 23. |
- 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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| 24. |
- Erlandsson, Malin, 1972, et al.
(författare)
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Survivin promotes a glycolytic switch in CD4+ T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis.
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:12
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we explore the role of nuclear survivin in maintaining the effector phenotype of IFNγ-producing Tcells acting through the transcriptional control of glucose utilization. High expression of survivin in CD4+T cells was associated with IFNγ-dependent phenotype and anaerobic glycolysis. Transcriptome of CD4+ cells and sequencing of survivin-bound chromatin showed that nuclear survivin had a genome-wide and motif-specific binding to regulatory regions of the genes controlling cell metabolism. Survivin coprecipitates with transcription factors IRF1 and SMAD3, which repressed the transcription of the metabolic check-point enzyme phosphofructokinase 2 gene PFKFB3 and promoted anaerobic glycolysis. Combining transcriptome analyses of CD4+ cells and functional studies in glucose metabolism, we demonstrated that the inhibition of survivin reverted PFKFB3 production, inhibited glucose uptake, and reduces interferon effects in CD4+ cells. These results present a survivin-dependent mechanism in coordinating the metabolic adaptation of CD4+T cells and propose an attractive strategy to counteract IFNγ-dependent inflammation in autoimmunity.
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| 25. |
- 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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