Exclusively neuron-centric approaches to neuropathological mechanisms have not resulted in major ... more Exclusively neuron-centric approaches to neuropathological mechanisms have not resulted in major new breakthroughs in the prevention and therapy of neurodegenerative diseases. In the present paper, we review the role of glia in neurodegeneration in an attempt to identify novel targets that could be used to develop much-needed strategies for the containment and cure of neurodegenerative disorders. We discuss this in the context of glial roles in the homoeostasis and defence of the brain. We consider the mounting evidence supporting a change away from the perception of reactive glial responses merely as secondary detrimental processes that exacerbate the course of neurological disorders, in favour of an emerging contemporary view of glial pathological responses as complex and multistaged defensive processes that also have the potential for dysfunction. Neuroglia: the homoeostatic arm of the central nervous system Neuroglia, represented by highly heterogeneous population of non-excitab...
As part of the innate immune system, complement plays a critical role in the elimination of patho... more As part of the innate immune system, complement plays a critical role in the elimination of pathogens and mobilization of cellular immune responses. In the central nervous system (CNS), many complement proteins are locally produced and regulate nervous system development and physiological processes such as neural plasticity. However, aberrant complement activation has been implicated in neurodegeneration, including Alzheimer’s disease. There is a growing list of pathogens that have been shown to interact with the complement system in the brain but the short- and long-term consequences of infection-induced complement activation for neuronal functioning are largely elusive. Available evidence suggests that the infection-induced complement activation could be protective or harmful, depending on the context. Here we summarize how various infectious agents, including bacteria (e.g., Streptococcus spp.), viruses (e.g., HIV and measles virus), fungi (e.g., Candida spp.), parasites (e.g., T...
Objective To examine the association between observer-assessed functional status and perceived re... more 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 (rs) 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, r...
Cellular and Molecular Approaches to Regeneration and Repair, 2017
Complement is part of the innate immune system that plays a major role in the initiation of infla... more Complement is part of the innate immune system that plays a major role in the initiation of inflammation and host defence against pathogenic bacteria. Complement activation is also a contributor to tissue damage in a range of autoimmune conditions. For those reasons, the activation of the complement system in the central nervous system (CNS) was for long considered deleterious. Based on the evidence accumulated during the past decade, this view has been dramatically changing and complement is gaining recognition for its non-immune surveillance related functions, including regulation of morphogenesis, and adult tissue regeneration. C3a is a 77 amino acid, 9 kDa peptide generated through the proteolytic activation of the central molecule of the complement system, the third complement component, C3. C3a exerts most of its functions through its canonical G-protein coupled receptor C3aR that is expressed by many cell types including neurons and glia. This chapter considers recent insights into the novel roles of the complement system, in particular C3a, in the CNS with focus on brain plasticity and recovery after ischemic brain injury.
ABSTRACT Astrocyte activation and reactive gliosis are seen in many neuropathologies, e.g., neuro... more ABSTRACT Astrocyte activation and reactive gliosis are seen in many neuropathologies, e.g., neurotrauma, stroke, epilepsy, or neurodegenerative diseases. Astrocyte activation alters gene expression and leads to morphological and functional changes in astrocytes with important functional consequences for the central nervous system (Eddleston and Mucke, Neuroscience 54:15-36, 1993; Eng and Ghirnikar, Brain Pathol 4:229-237, 1994; Hernandez et al., Glia 38:45-64, 2002; Pekny and Nilsson, Glia 50:427-434, 2005; Wilhelmsson et al., Proc Natl Acad Sci U S A 103:17513-17518, 2006; Sofroniew, Trends Neurosci 32:638-647, 2009; Sofroniew and Vinters, Acta Neuropathol 119:7-35, 2010). The understanding of astrocyte activation and reactive gliosis in pathological situations remains incomplete but the increasing amount of experimental evidence points to its importance in disease pathogenesis (Wilhelmsson et al., J Neurosci 24:5016-5021, 2004; Sofroniew, Neuroscientist 11:400-407, 2005; Maragakis and Rothstein, Nat Clin Pract Neurol 2:679-689, 2006; Seifert et al., Nat Rev Neurosci 7:194-206, 2006; Correa-Cerro and Mandell, J Neuropathol Exp Neurol 66:169-76, 2007; Barres, Neuron 60:430-440, 2008; Li et al., J Cereb Blood Flow Metab 28:468-481, 2008; Macauley et al. J Neurosci 31:15575-15585, 2011). One of the principal hallmarks of astrocyte activation and reactive gliosis is the upregulation of astrocyte intermediate filament (nanofilament) proteins and reorganization of intermediate filaments that are part of the cytoskeleton. This review focuses on the role of the intermediate filament system of astrocytes in neuropathological context and presents some of the relevant model systems.
In neurotrauma, brain ischemia or neurodegenerative diseases, astrocytes become reactive (which i... more In neurotrauma, brain ischemia or neurodegenerative diseases, astrocytes become reactive (which is known as reactive gliosis) and this is accompanied by an altered expression of many genes. Two cellular hallmarks of reactive gliosis are hypertrophy of astrocyte processes and the upregulation of the part of the cytoskeleton known as intermediate filaments, which are composed of nestin, vimentin, and GFAP. Our aim has been to better understand the function of reactive astrocytes in CNS diseases. Using mice deficient for astrocyte intermediate filaments (GFAP(-/-)Vim(-/-)), we were able to attenuate reactive gliosis and slow down the healing process after neurotrauma. We demonstrated the key role of reactive astrocytes in neurotrauma-at an early stage after neurotrauma, reactive astrocytes have a neuroprotective effect; at a later stage, they facilitate the formation of posttraumatic glial scars and inhibit CNS regeneration, specifically, they seem to compromise neural graft survival and integration, reduce the extent of synaptic regeneration, inhibit neurogenesis in the old age, and inhibit regeneration of severed CNS axons. We propose that reactive astrocytes are the future target for the therapeutic strategies promoting regeneration and plasticity in the brain and spinal cord in various disease conditions. Through its involvement in inflammation, opsonization, and cytolysis, complement protects against infectious agents. Although most of the complement proteins are synthesized in CNS, the role of the complement system in the normal or ischemic CNS remains unclear. Complement activiation in the CNS has been generally considered as contributing to tissue damage. However, growing body of evidence suggests that complement may be a physiological neuroprotective mechanism as well as it may participate in maintenance and repair of the adult brain.
Complement is an essential component of inflammation that plays a role in ischemic brain injury. ... more Complement is an essential component of inflammation that plays a role in ischemic brain injury. Recent reports demonstrate novel functions of complement in normal and diseased CNS, such as regulation of neurogenesis and synapse elimination. Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI), a model of neonatal HI encephalopathy. HI injury was induced at postnatal day 9 (P9), and loss of hippocampal tissue was determined on P31. We compared WT mice with transgenic mice expressing C3a under the control of glial fibrillary acidic protein promoter, which express biologically active C3a only in CNS and without the requirement of a priori complement activation. Further, we injected C3a peptide into the lateral cerebral ventricle of mice lacking the C3a receptor (C3aR) and WT mice and assessed HI-induced memory impairment 41 d later. We found that HI-induced tissue loss in C3a overexpressing mice was reduced by 50% compared with WT mice. C3a peptide injected 1 h after HI protected WT but not C3aR-deficient mice against HI-induced memory impairment. Thus, C3a acting through its canonical receptor ameliorates behavioral deficits after HI injury, and C3aR is a novel therapeutic target for the treatment of neonatal HI encephalopathy.
We tested the hypothesis that astrocytes grown in a suitable three-dimensional (3D) cell culture ... more We tested the hypothesis that astrocytes grown in a suitable three-dimensional (3D) cell culture system exhibit morphological and biochemical features of in vivo astrocytes that are otherwise lost upon transfer from the in vivo to a two-dimensional (2D) culture environment. First, we report development of a novel bioactively coated nanofiber-based 3D culture system (Bioactive3D) that supports cultures of primary mouse astrocytes. Second, we show that Bioactive3D culture system maintains the in vivo-like morphological complexity of cultured cells, allows movement of astrocyte filopodia in a way that resembles the in vivo situation, and also minimizes the cellular stress, an inherent feature of standard 2D cell culture systems. Third, we demonstrate that the expression of gap junctions is reduced in astrocytes cultured in a 3D system that supports well-organized cell-cell communication, in contrast to the enforced planar tiling of cells in a standard 2D system. Finally, we show that astrocytes cultured in the Bioactive3D system do not show the undesired baseline activation but are fully responsive to activation-inducing stimuli. Thus, astrocytes cultured in the Bioactive3D appear to more closely resemble astrocytes in vivo and represent a superior in vitro system for assessing (patho)physiological and pharmacological responses of these cells and potentially also in co-cultures of astrocytes and other cell types.
Exclusively neuron-centric approaches to neuropathological mechanisms have not resulted in major ... more Exclusively neuron-centric approaches to neuropathological mechanisms have not resulted in major new breakthroughs in the prevention and therapy of neurodegenerative diseases. In the present paper, we review the role of glia in neurodegeneration in an attempt to identify novel targets that could be used to develop much-needed strategies for the containment and cure of neurodegenerative disorders. We discuss this in the context of glial roles in the homoeostasis and defence of the brain. We consider the mounting evidence supporting a change away from the perception of reactive glial responses merely as secondary detrimental processes that exacerbate the course of neurological disorders, in favour of an emerging contemporary view of glial pathological responses as complex and multistaged defensive processes that also have the potential for dysfunction. Neuroglia: the homoeostatic arm of the central nervous system Neuroglia, represented by highly heterogeneous population of non-excitab...
As part of the innate immune system, complement plays a critical role in the elimination of patho... more As part of the innate immune system, complement plays a critical role in the elimination of pathogens and mobilization of cellular immune responses. In the central nervous system (CNS), many complement proteins are locally produced and regulate nervous system development and physiological processes such as neural plasticity. However, aberrant complement activation has been implicated in neurodegeneration, including Alzheimer’s disease. There is a growing list of pathogens that have been shown to interact with the complement system in the brain but the short- and long-term consequences of infection-induced complement activation for neuronal functioning are largely elusive. Available evidence suggests that the infection-induced complement activation could be protective or harmful, depending on the context. Here we summarize how various infectious agents, including bacteria (e.g., Streptococcus spp.), viruses (e.g., HIV and measles virus), fungi (e.g., Candida spp.), parasites (e.g., T...
Objective To examine the association between observer-assessed functional status and perceived re... more 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 (rs) 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, r...
Cellular and Molecular Approaches to Regeneration and Repair, 2017
Complement is part of the innate immune system that plays a major role in the initiation of infla... more Complement is part of the innate immune system that plays a major role in the initiation of inflammation and host defence against pathogenic bacteria. Complement activation is also a contributor to tissue damage in a range of autoimmune conditions. For those reasons, the activation of the complement system in the central nervous system (CNS) was for long considered deleterious. Based on the evidence accumulated during the past decade, this view has been dramatically changing and complement is gaining recognition for its non-immune surveillance related functions, including regulation of morphogenesis, and adult tissue regeneration. C3a is a 77 amino acid, 9 kDa peptide generated through the proteolytic activation of the central molecule of the complement system, the third complement component, C3. C3a exerts most of its functions through its canonical G-protein coupled receptor C3aR that is expressed by many cell types including neurons and glia. This chapter considers recent insights into the novel roles of the complement system, in particular C3a, in the CNS with focus on brain plasticity and recovery after ischemic brain injury.
ABSTRACT Astrocyte activation and reactive gliosis are seen in many neuropathologies, e.g., neuro... more ABSTRACT Astrocyte activation and reactive gliosis are seen in many neuropathologies, e.g., neurotrauma, stroke, epilepsy, or neurodegenerative diseases. Astrocyte activation alters gene expression and leads to morphological and functional changes in astrocytes with important functional consequences for the central nervous system (Eddleston and Mucke, Neuroscience 54:15-36, 1993; Eng and Ghirnikar, Brain Pathol 4:229-237, 1994; Hernandez et al., Glia 38:45-64, 2002; Pekny and Nilsson, Glia 50:427-434, 2005; Wilhelmsson et al., Proc Natl Acad Sci U S A 103:17513-17518, 2006; Sofroniew, Trends Neurosci 32:638-647, 2009; Sofroniew and Vinters, Acta Neuropathol 119:7-35, 2010). The understanding of astrocyte activation and reactive gliosis in pathological situations remains incomplete but the increasing amount of experimental evidence points to its importance in disease pathogenesis (Wilhelmsson et al., J Neurosci 24:5016-5021, 2004; Sofroniew, Neuroscientist 11:400-407, 2005; Maragakis and Rothstein, Nat Clin Pract Neurol 2:679-689, 2006; Seifert et al., Nat Rev Neurosci 7:194-206, 2006; Correa-Cerro and Mandell, J Neuropathol Exp Neurol 66:169-76, 2007; Barres, Neuron 60:430-440, 2008; Li et al., J Cereb Blood Flow Metab 28:468-481, 2008; Macauley et al. J Neurosci 31:15575-15585, 2011). One of the principal hallmarks of astrocyte activation and reactive gliosis is the upregulation of astrocyte intermediate filament (nanofilament) proteins and reorganization of intermediate filaments that are part of the cytoskeleton. This review focuses on the role of the intermediate filament system of astrocytes in neuropathological context and presents some of the relevant model systems.
In neurotrauma, brain ischemia or neurodegenerative diseases, astrocytes become reactive (which i... more In neurotrauma, brain ischemia or neurodegenerative diseases, astrocytes become reactive (which is known as reactive gliosis) and this is accompanied by an altered expression of many genes. Two cellular hallmarks of reactive gliosis are hypertrophy of astrocyte processes and the upregulation of the part of the cytoskeleton known as intermediate filaments, which are composed of nestin, vimentin, and GFAP. Our aim has been to better understand the function of reactive astrocytes in CNS diseases. Using mice deficient for astrocyte intermediate filaments (GFAP(-/-)Vim(-/-)), we were able to attenuate reactive gliosis and slow down the healing process after neurotrauma. We demonstrated the key role of reactive astrocytes in neurotrauma-at an early stage after neurotrauma, reactive astrocytes have a neuroprotective effect; at a later stage, they facilitate the formation of posttraumatic glial scars and inhibit CNS regeneration, specifically, they seem to compromise neural graft survival and integration, reduce the extent of synaptic regeneration, inhibit neurogenesis in the old age, and inhibit regeneration of severed CNS axons. We propose that reactive astrocytes are the future target for the therapeutic strategies promoting regeneration and plasticity in the brain and spinal cord in various disease conditions. Through its involvement in inflammation, opsonization, and cytolysis, complement protects against infectious agents. Although most of the complement proteins are synthesized in CNS, the role of the complement system in the normal or ischemic CNS remains unclear. Complement activiation in the CNS has been generally considered as contributing to tissue damage. However, growing body of evidence suggests that complement may be a physiological neuroprotective mechanism as well as it may participate in maintenance and repair of the adult brain.
Complement is an essential component of inflammation that plays a role in ischemic brain injury. ... more Complement is an essential component of inflammation that plays a role in ischemic brain injury. Recent reports demonstrate novel functions of complement in normal and diseased CNS, such as regulation of neurogenesis and synapse elimination. Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI), a model of neonatal HI encephalopathy. HI injury was induced at postnatal day 9 (P9), and loss of hippocampal tissue was determined on P31. We compared WT mice with transgenic mice expressing C3a under the control of glial fibrillary acidic protein promoter, which express biologically active C3a only in CNS and without the requirement of a priori complement activation. Further, we injected C3a peptide into the lateral cerebral ventricle of mice lacking the C3a receptor (C3aR) and WT mice and assessed HI-induced memory impairment 41 d later. We found that HI-induced tissue loss in C3a overexpressing mice was reduced by 50% compared with WT mice. C3a peptide injected 1 h after HI protected WT but not C3aR-deficient mice against HI-induced memory impairment. Thus, C3a acting through its canonical receptor ameliorates behavioral deficits after HI injury, and C3aR is a novel therapeutic target for the treatment of neonatal HI encephalopathy.
We tested the hypothesis that astrocytes grown in a suitable three-dimensional (3D) cell culture ... more We tested the hypothesis that astrocytes grown in a suitable three-dimensional (3D) cell culture system exhibit morphological and biochemical features of in vivo astrocytes that are otherwise lost upon transfer from the in vivo to a two-dimensional (2D) culture environment. First, we report development of a novel bioactively coated nanofiber-based 3D culture system (Bioactive3D) that supports cultures of primary mouse astrocytes. Second, we show that Bioactive3D culture system maintains the in vivo-like morphological complexity of cultured cells, allows movement of astrocyte filopodia in a way that resembles the in vivo situation, and also minimizes the cellular stress, an inherent feature of standard 2D cell culture systems. Third, we demonstrate that the expression of gap junctions is reduced in astrocytes cultured in a 3D system that supports well-organized cell-cell communication, in contrast to the enforced planar tiling of cells in a standard 2D system. Finally, we show that astrocytes cultured in the Bioactive3D system do not show the undesired baseline activation but are fully responsive to activation-inducing stimuli. Thus, astrocytes cultured in the Bioactive3D appear to more closely resemble astrocytes in vivo and represent a superior in vitro system for assessing (patho)physiological and pharmacological responses of these cells and potentially also in co-cultures of astrocytes and other cell types.
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Papers by Marcela Pekna