Katerina Akassoglou - Academia.edu (original) (raw)
Papers by Katerina Akassoglou
F1000 - Post-publication peer review of the biomedical literature, 2012
F1000 - Post-publication peer review of the biomedical literature, 2013
F1000 - Post-publication peer review of the biomedical literature, 2014
F1000 - Post-publication peer review of the biomedical literature, 2012
The Journal of Cell Biology, May 29, 2000
Tissue plasminogen activator (tPA) is a serine protease that converts plasminogen to plasmin and ... more Tissue plasminogen activator (tPA) is a serine protease that converts plasminogen to plasmin and can trigger the degradation of extracellular matrix proteins. In the nervous system, under noninflammatory conditions, tPA contributes to excitotoxic neuronal death, probably through degradation of laminin. To evaluate the contribution of extracellular proteolysis in inflammatory neuronal degeneration, we performed sciatic nerve injury in mice. Proteolytic activity was increased in the nerve after injury, and this activity was primarily because of Schwann cell-produced tPA.
Amer J Physiol Heart Circ Phy, 2007
In recent years, transgenic mouse models have been developed to examine the underlying cellular a... more In recent years, transgenic mouse models have been developed to examine the underlying cellular and molecular mechanisms of lung disease and pulmonary vascular disease, such as asthma, pulmonary thromboembolic disease, and pulmonary hypertension. However, there has not been systematic characterization of the basic physiological pulmonary vascular reactivity in normal and transgenic mice. This represents an intellectual "gap", since it is important to characterize basic murine pulmonary vascular reactivity in response to various contractile and relaxant factors to which the pulmonary vasculature is exposed under physiological conditions. The present study evaluates excitation- and pharmacomechanical-contraction coupling in pulmonary arteries (PA) isolated from wild-type BALB/c mice. We demonstrate that both pharmaco- and electromechanical coupling mechanisms exist in mice PA. These arteries are also reactive to stimulation by alpha(1)-adrenergic agonists, serotonin, endothelin-1, vasopressin, and U-46619 (a thromboxane A(2) analog). We conclude that the basic vascular responsiveness of mouse PA is similar to those observed in PA of other species, including rat, pig, and human, albeit on a different scale and to varying amplitudes.
Current Medicinal Chemistry, Oct 31, 2007
The blood protein fibrinogen as a ligand for integrin and non-integrin receptors functions as the... more The blood protein fibrinogen as a ligand for integrin and non-integrin receptors functions as the molecular nexus of coagulation, inflammation and immunity. Studies in animal models and in human disease have demonstrated that extravascular fibrinogen that is deposited in tissues upon vascular rupture is not merely a marker, but a mediator of diseases with an inflammatory component, such as rheumatoid arthritis, multiple sclerosis, sepsis, myocardial infarction and bacterial infection. The present article focuses on the recent discoveries of specific cellular targets and receptors for fibrinogen within tissues that have extended the role of fibrinogen from a coagulation factor to a regulator of inflammation and immunity. Fibrinogen has the potential for selective drug targeting that would target its proinflammatory properties without affecting its beneficial effects in hemostasis, since it interacts with different receptors to mediate blood coagulation and inflammation. Strategies to target receptors for fibrinogen and fibrin within the tissue microenvironment could reveal selective and disease-specific agents for therapeutic intervention in a variety of human diseases associated with fibrin deposition.
J Neuroimmunol, 1997
Tumour necrosis factor-α (TNF-α) plays a central role in inflammatory events including those taki... more Tumour necrosis factor-α (TNF-α) plays a central role in inflammatory events including those taking place in the central nervous system (CNS), and has been implicated as a key pathogenicc mediator in several human inflammatory, infectious and autoimmune CNS disorders. Using transgenic and gene knockout mice we have investigated the role of deregulated TNF-α production in the CNS. We show that the overexpression of wild-type murine or human TNF-α transgenes by resident CNS astrocytes or neurons in sufficient to trigger a neurological disorder characterised by ataxia, seizures and paresis, with histopathological features of chronic CNS inflammation and white matter degeneration. Furthermore, we show that transmembrane human TNF-α is sufficient to trigger CNS inflammation and degeneration when overexpressed by astrocytes but not by neurons, indicating that target cells mediating the neuroinflammatory activities of TNF-α localise in the vicinity of astrocytes rather than neurons. Our results establish that both soluble and transmembrane molecular forms of TNF-α can play critical roles in vivo in the pathogenesis of CNS inflammation and demyelination, and validate TNF-α transgenic and mutant mice as important models for the further study of related human CNS diseases.
Frontiers in cellular neuroscience, 2015
Blood proteins at the neurovascular unit (NVU) are emerging as important molecular determinants o... more Blood proteins at the neurovascular unit (NVU) are emerging as important molecular determinants of communication between the brain and the immune system. Over the past two decades, roles for the plasminogen activation (PA)/plasmin system in fibrinolysis have been extended from peripheral dissolution of blood clots to the regulation of central nervous system (CNS) functions in physiology and disease. In this review, we discuss how fibrin and its proteolytic degradation affect neuroinflammatory, degenerative and repair processes. In particular, we focus on novel functions of fibrin-the final product of the coagulation cascade and the main substrate of plasmin-in the activation of immune responses and trafficking of immune cells into the brain. We also comment on the suitability of the coagulation and fibrinolytic systems as potential biomarkers and drug targets in diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and stroke. Studying coagulation and fibrinolysis ...
Nature Neuroscience, 2015
Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotro... more Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotrophin receptor (p75(NTR)) is a component of the nuclear pore complex (NPC) required for glial scar formation and reduced gamma oscillations in mice via regulation of transforming growth factor (TGF)-β signaling. Cleaved p75(NTR) interacts with nucleoporins to promote Smad2 nucleocytoplasmic shuttling. Thus, NPC remodeling by regulated intramembrane cleavage of p75(NTR) controls astrocyte-neuronal communication in response to profibrotic factors.
Journal of Experimental Medicine, 2015
WT or H363Y mutant SIRT1 was immunoprecipitated from transfected 293T cells and probed as indicat... more WT or H363Y mutant SIRT1 was immunoprecipitated from transfected 293T cells and probed as indicated. (B) RORt was immunoprecipitated from thymocytes and Th17 cells, and probed with antibody against SIRT1. (C) Immunoprecipitation using lysates of 293T cells co-transfected with constructs encoding SIRT1 and various deletion mutants of RORt. Relative binding was calculated by normalizing the ratio of immunoprecipitated RORt/SIRT1 to the ratio of input RORt/SIRT1. (D) Acetylation of Flag-tagged RORt immunoprecipitated from 293T cells transfected with various acetyltransferases and Flag-RORt. (E and F) Acetylation of Flag-RORt co-transfected with p300 and WT or H363Y mutant SIRT1, in the absence (E) or in the presence (F) of nicotinamide and Ex-527. Equal amounts of Flag-RORt were loaded (D-F). Representative data are shown from four (A), three (B and E), and two (D) independent experiments, and combined data are shown from three (C and F) independent experiments with error bars representing ±SEM.
eNeuro, 2015
Hypoxia-like tissue alterations, characterized by the upregulation of hypoxia-inducible factor-1α... more Hypoxia-like tissue alterations, characterized by the upregulation of hypoxia-inducible factor-1α (HIF-1α), have been described in the normal appearing white matter and pre-demyelinating lesions of multiple sclerosis (MS) patients. As HIF-1α regulates the transcription of a wide set of genes involved in neuroprotection and neuroinflammation, HIF-1α expression may contribute to the pathogenesis of inflammatory demyelination. To test this hypothesis, we analyzed the effect of cell-specific genetic ablation or overexpression of HIF-1α on the onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. HIF-1α was mainly expressed in astrocytes and microglia/macrophages in the mouse spinal cord at the peak of EAE. However, genetic ablation of HIF-1α in astrocytes and/or myeloid cells did not ameliorate clinical symptoms. Furthermore, conditional knock-out of Von Hippel Lindau, a negative regulator of HIF-1α stabilization, failed to exacerbate the clinical course of EAE. In accordance with clinical symptoms, genetic ablation or overexpression of HIF-1α did not change the extent of spinal cord inflammation and demyelination. Overall, our data indicate that despite dramatic upregulation of HIF-1α in astrocytes and myeloid cells in EAE, HIF-1α expression in these two cell types is not required for the development of inflammatory demyelination. Despite numerous reports indicating HIF-1α expression in glia, neurons, and inflammatory cells in the CNS of MS patients, the cell-specific contribution of HIF-1α to disease pathogenesis remains unclear. Here we show that although HIF-1α is dramatically upregulated in astrocytes and myeloid cells in EAE, cell-specific depletion of HIF-1α in these two cell types surprisingly does not affect the development of neuroinflammatory disease. Together with two recently published studies showing a role for oligodendrocyte-specific HIF-1α in myelination and T-cell-specific HIF-1α in EAE, our results demonstrate a tightly regulated cellular specificity for HIF-1α contribution in nervous system pathogenesis.
Central Nervous System Diseases and Inflammation, 2008
Imaging Microglia in the Central Nervous System: Past, Present and Future Dimitrios Davalos and K... more Imaging Microglia in the Central Nervous System: Past, Present and Future Dimitrios Davalos and Katerina Akassoglou ... Microglia display a highly branched morphology in the unperturbed cerebral cortex, with each cell soma decorated by long processes with fine termini. ...
Neuroimmunodegeneration, 1998
Intravital, 2012
The neurovascular unit-comprised of glia, pericytes, neurons and cerebrovasculature-is a dynamic ... more The neurovascular unit-comprised of glia, pericytes, neurons and cerebrovasculature-is a dynamic interface that ensures physiological central nervous system (CNS) functioning. In disease dynamic remodeling of the neurovascular interface triggers a cascade of responses that determine the extent of CNS degeneration and repair. The dynamics of these processes can be adequately captured by imaging in vivo, which allows the study of cellular responses to environmental stimuli and cell-cell interactions in the living brain in real time. This perspective focuses on intravital imaging studies of the neurovascular unit in stroke, multiple sclerosis (MS) and Alzheimer disease (AD) models and discusses their potential for identifying novel therapeutic targets.
Journal of visualized experiments : JoVE, 2012
In vivo imaging using two-photon microscopy in mice that have been genetically engineered to expr... more In vivo imaging using two-photon microscopy in mice that have been genetically engineered to express fluorescent proteins in specific cell types has significantly broadened our knowledge of physiological and pathological processes in numerous tissues in vivo. In studies of the central nervous system (CNS), there has been a broad application of in vivo imaging in the brain, which has produced a plethora of novel and often unexpected findings about the behavior of cells such as neurons, astrocytes, microglia, under physiological or pathological conditions. However, mostly technical complications have limited the implementation of in vivo imaging in studies of the living mouse spinal cord. In particular, the anatomical proximity of the spinal cord to the lungs and heart generates significant movement artifact that makes imaging the living spinal cord a challenging task. We developed a novel method that overcomes the inherent limitations of spinal cord imaging by stabilizing the spinal ...
F1000 - Post-publication peer review of the biomedical literature, 2012
F1000 - Post-publication peer review of the biomedical literature, 2013
F1000 - Post-publication peer review of the biomedical literature, 2014
F1000 - Post-publication peer review of the biomedical literature, 2012
The Journal of Cell Biology, May 29, 2000
Tissue plasminogen activator (tPA) is a serine protease that converts plasminogen to plasmin and ... more Tissue plasminogen activator (tPA) is a serine protease that converts plasminogen to plasmin and can trigger the degradation of extracellular matrix proteins. In the nervous system, under noninflammatory conditions, tPA contributes to excitotoxic neuronal death, probably through degradation of laminin. To evaluate the contribution of extracellular proteolysis in inflammatory neuronal degeneration, we performed sciatic nerve injury in mice. Proteolytic activity was increased in the nerve after injury, and this activity was primarily because of Schwann cell-produced tPA.
Amer J Physiol Heart Circ Phy, 2007
In recent years, transgenic mouse models have been developed to examine the underlying cellular a... more In recent years, transgenic mouse models have been developed to examine the underlying cellular and molecular mechanisms of lung disease and pulmonary vascular disease, such as asthma, pulmonary thromboembolic disease, and pulmonary hypertension. However, there has not been systematic characterization of the basic physiological pulmonary vascular reactivity in normal and transgenic mice. This represents an intellectual "gap", since it is important to characterize basic murine pulmonary vascular reactivity in response to various contractile and relaxant factors to which the pulmonary vasculature is exposed under physiological conditions. The present study evaluates excitation- and pharmacomechanical-contraction coupling in pulmonary arteries (PA) isolated from wild-type BALB/c mice. We demonstrate that both pharmaco- and electromechanical coupling mechanisms exist in mice PA. These arteries are also reactive to stimulation by alpha(1)-adrenergic agonists, serotonin, endothelin-1, vasopressin, and U-46619 (a thromboxane A(2) analog). We conclude that the basic vascular responsiveness of mouse PA is similar to those observed in PA of other species, including rat, pig, and human, albeit on a different scale and to varying amplitudes.
Current Medicinal Chemistry, Oct 31, 2007
The blood protein fibrinogen as a ligand for integrin and non-integrin receptors functions as the... more The blood protein fibrinogen as a ligand for integrin and non-integrin receptors functions as the molecular nexus of coagulation, inflammation and immunity. Studies in animal models and in human disease have demonstrated that extravascular fibrinogen that is deposited in tissues upon vascular rupture is not merely a marker, but a mediator of diseases with an inflammatory component, such as rheumatoid arthritis, multiple sclerosis, sepsis, myocardial infarction and bacterial infection. The present article focuses on the recent discoveries of specific cellular targets and receptors for fibrinogen within tissues that have extended the role of fibrinogen from a coagulation factor to a regulator of inflammation and immunity. Fibrinogen has the potential for selective drug targeting that would target its proinflammatory properties without affecting its beneficial effects in hemostasis, since it interacts with different receptors to mediate blood coagulation and inflammation. Strategies to target receptors for fibrinogen and fibrin within the tissue microenvironment could reveal selective and disease-specific agents for therapeutic intervention in a variety of human diseases associated with fibrin deposition.
J Neuroimmunol, 1997
Tumour necrosis factor-α (TNF-α) plays a central role in inflammatory events including those taki... more Tumour necrosis factor-α (TNF-α) plays a central role in inflammatory events including those taking place in the central nervous system (CNS), and has been implicated as a key pathogenicc mediator in several human inflammatory, infectious and autoimmune CNS disorders. Using transgenic and gene knockout mice we have investigated the role of deregulated TNF-α production in the CNS. We show that the overexpression of wild-type murine or human TNF-α transgenes by resident CNS astrocytes or neurons in sufficient to trigger a neurological disorder characterised by ataxia, seizures and paresis, with histopathological features of chronic CNS inflammation and white matter degeneration. Furthermore, we show that transmembrane human TNF-α is sufficient to trigger CNS inflammation and degeneration when overexpressed by astrocytes but not by neurons, indicating that target cells mediating the neuroinflammatory activities of TNF-α localise in the vicinity of astrocytes rather than neurons. Our results establish that both soluble and transmembrane molecular forms of TNF-α can play critical roles in vivo in the pathogenesis of CNS inflammation and demyelination, and validate TNF-α transgenic and mutant mice as important models for the further study of related human CNS diseases.
Frontiers in cellular neuroscience, 2015
Blood proteins at the neurovascular unit (NVU) are emerging as important molecular determinants o... more Blood proteins at the neurovascular unit (NVU) are emerging as important molecular determinants of communication between the brain and the immune system. Over the past two decades, roles for the plasminogen activation (PA)/plasmin system in fibrinolysis have been extended from peripheral dissolution of blood clots to the regulation of central nervous system (CNS) functions in physiology and disease. In this review, we discuss how fibrin and its proteolytic degradation affect neuroinflammatory, degenerative and repair processes. In particular, we focus on novel functions of fibrin-the final product of the coagulation cascade and the main substrate of plasmin-in the activation of immune responses and trafficking of immune cells into the brain. We also comment on the suitability of the coagulation and fibrinolytic systems as potential biomarkers and drug targets in diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and stroke. Studying coagulation and fibrinolysis ...
Nature Neuroscience, 2015
Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotro... more Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotrophin receptor (p75(NTR)) is a component of the nuclear pore complex (NPC) required for glial scar formation and reduced gamma oscillations in mice via regulation of transforming growth factor (TGF)-β signaling. Cleaved p75(NTR) interacts with nucleoporins to promote Smad2 nucleocytoplasmic shuttling. Thus, NPC remodeling by regulated intramembrane cleavage of p75(NTR) controls astrocyte-neuronal communication in response to profibrotic factors.
Journal of Experimental Medicine, 2015
WT or H363Y mutant SIRT1 was immunoprecipitated from transfected 293T cells and probed as indicat... more WT or H363Y mutant SIRT1 was immunoprecipitated from transfected 293T cells and probed as indicated. (B) RORt was immunoprecipitated from thymocytes and Th17 cells, and probed with antibody against SIRT1. (C) Immunoprecipitation using lysates of 293T cells co-transfected with constructs encoding SIRT1 and various deletion mutants of RORt. Relative binding was calculated by normalizing the ratio of immunoprecipitated RORt/SIRT1 to the ratio of input RORt/SIRT1. (D) Acetylation of Flag-tagged RORt immunoprecipitated from 293T cells transfected with various acetyltransferases and Flag-RORt. (E and F) Acetylation of Flag-RORt co-transfected with p300 and WT or H363Y mutant SIRT1, in the absence (E) or in the presence (F) of nicotinamide and Ex-527. Equal amounts of Flag-RORt were loaded (D-F). Representative data are shown from four (A), three (B and E), and two (D) independent experiments, and combined data are shown from three (C and F) independent experiments with error bars representing ±SEM.
eNeuro, 2015
Hypoxia-like tissue alterations, characterized by the upregulation of hypoxia-inducible factor-1α... more Hypoxia-like tissue alterations, characterized by the upregulation of hypoxia-inducible factor-1α (HIF-1α), have been described in the normal appearing white matter and pre-demyelinating lesions of multiple sclerosis (MS) patients. As HIF-1α regulates the transcription of a wide set of genes involved in neuroprotection and neuroinflammation, HIF-1α expression may contribute to the pathogenesis of inflammatory demyelination. To test this hypothesis, we analyzed the effect of cell-specific genetic ablation or overexpression of HIF-1α on the onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. HIF-1α was mainly expressed in astrocytes and microglia/macrophages in the mouse spinal cord at the peak of EAE. However, genetic ablation of HIF-1α in astrocytes and/or myeloid cells did not ameliorate clinical symptoms. Furthermore, conditional knock-out of Von Hippel Lindau, a negative regulator of HIF-1α stabilization, failed to exacerbate the clinical course of EAE. In accordance with clinical symptoms, genetic ablation or overexpression of HIF-1α did not change the extent of spinal cord inflammation and demyelination. Overall, our data indicate that despite dramatic upregulation of HIF-1α in astrocytes and myeloid cells in EAE, HIF-1α expression in these two cell types is not required for the development of inflammatory demyelination. Despite numerous reports indicating HIF-1α expression in glia, neurons, and inflammatory cells in the CNS of MS patients, the cell-specific contribution of HIF-1α to disease pathogenesis remains unclear. Here we show that although HIF-1α is dramatically upregulated in astrocytes and myeloid cells in EAE, cell-specific depletion of HIF-1α in these two cell types surprisingly does not affect the development of neuroinflammatory disease. Together with two recently published studies showing a role for oligodendrocyte-specific HIF-1α in myelination and T-cell-specific HIF-1α in EAE, our results demonstrate a tightly regulated cellular specificity for HIF-1α contribution in nervous system pathogenesis.
Central Nervous System Diseases and Inflammation, 2008
Imaging Microglia in the Central Nervous System: Past, Present and Future Dimitrios Davalos and K... more Imaging Microglia in the Central Nervous System: Past, Present and Future Dimitrios Davalos and Katerina Akassoglou ... Microglia display a highly branched morphology in the unperturbed cerebral cortex, with each cell soma decorated by long processes with fine termini. ...
Neuroimmunodegeneration, 1998
Intravital, 2012
The neurovascular unit-comprised of glia, pericytes, neurons and cerebrovasculature-is a dynamic ... more The neurovascular unit-comprised of glia, pericytes, neurons and cerebrovasculature-is a dynamic interface that ensures physiological central nervous system (CNS) functioning. In disease dynamic remodeling of the neurovascular interface triggers a cascade of responses that determine the extent of CNS degeneration and repair. The dynamics of these processes can be adequately captured by imaging in vivo, which allows the study of cellular responses to environmental stimuli and cell-cell interactions in the living brain in real time. This perspective focuses on intravital imaging studies of the neurovascular unit in stroke, multiple sclerosis (MS) and Alzheimer disease (AD) models and discusses their potential for identifying novel therapeutic targets.
Journal of visualized experiments : JoVE, 2012
In vivo imaging using two-photon microscopy in mice that have been genetically engineered to expr... more In vivo imaging using two-photon microscopy in mice that have been genetically engineered to express fluorescent proteins in specific cell types has significantly broadened our knowledge of physiological and pathological processes in numerous tissues in vivo. In studies of the central nervous system (CNS), there has been a broad application of in vivo imaging in the brain, which has produced a plethora of novel and often unexpected findings about the behavior of cells such as neurons, astrocytes, microglia, under physiological or pathological conditions. However, mostly technical complications have limited the implementation of in vivo imaging in studies of the living mouse spinal cord. In particular, the anatomical proximity of the spinal cord to the lungs and heart generates significant movement artifact that makes imaging the living spinal cord a challenging task. We developed a novel method that overcomes the inherent limitations of spinal cord imaging by stabilizing the spinal ...