Tissue plasminogen activator gene expression in multiple sclerosis brain tissue

Akenami, F.O.T.; Sirén, Vappu; Wessman, Maija; Koskiniemi, Marjaleena; Vaheri, Antti

doi:10.1016/s0022-510x(99)00080-5

Cited by 24 publications

(17 citation statements)

References 34 publications

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“…7,33,34 To investigate how the levels of tPA, uPA, and PAI-1 change during the course of EAE disease, ELISAs were performed on spinal cord protein extracts. Levels of tPA did not change throughout the course of EAE disease in WT and uPAR Ϫ/Ϫ mice (data not shown).…”

Section: Increased Pai-1 and Upa Levels During Eaementioning

confidence: 99%

A Role for the Plasminogen Activator System in Inflammation and Neurodegeneration in the Central Nervous System during Experimental Allergic Encephalomyelitis

East

Baker

Pryce

et al. 2005

The American Journal of Pathology

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Early signs of inflammatory demyelination include entry of fibrin(ogen) into the central nervous system (CNS), which is normally excluded by the blood-brain barrier, and up-regulation of components of the plasminogen activator system. Using mice deficient in tissue-type plasminogen activator (tPA ؊/؊ ) and urokinase plasminogen activator receptor (uPAR ؊/؊ ), we investigated the involvement of the PA system on the clinical and pathological features of experimental allergic encephalomyelitis, an animal model of multiple sclerosis. tPA ؊/؊ mice suffered an early and a more severe acute disease characterized by incomplete recovery when compared to wild-type controls, with significantly higher CNS levels of plasminogen activator inhibitor-1. This correlated with fibrin accumulation, which co-localized with nonphosphorylated neurofilament on thickened axons in experimental allergic encephalomyelitis tissue. In contrast, uPAR ؊/؊ mice had a delayed, less acute disease reflected in delayed infiltration of inflammatory cells. These animals developed chronic disease as a result of steadily increased inflammation, increased levels of urokinase-type plasminogen activator (uPA), and greater degree of demyelination. Thus, the plasminogen activator system can modulate both inflammatory and degenerative events in the CNS through the respective effects of tPA and uPAR on fibrinolysis and cell adhesion/migration, manipulation of which may have therapeutic implications for multiple sclerosis. Serine protease activity in multiple sclerosis (MS) is considered to play a major role in the disturbance of the blood-brain barrier and subsequent leukocyte entry leading to inflammation as well as causing myelin breakdown.1,2 Significant up-regulation of urokinase-type plasminogen activator (uPA) receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) are among the earliest detectable signs of inflammatory demyelination.

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Section: Increased Pai-1 and Upa Levels During Eaementioning

confidence: 99%

A Role for the Plasminogen Activator System in Inflammation and Neurodegeneration in the Central Nervous System during Experimental Allergic Encephalomyelitis

East

Baker

Pryce

et al. 2005

The American Journal of Pathology

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“…Although considerable progress has been made in understanding the genetic susceptibility and pathogenesis of this disease, there is still no uniformly effective treatment strategy [15,18]. The enzymatic digestion of the blood brain barrier and myelin protein by serine proteases is known to contribute to the development and progression of MS and EAE [1,12,19]. The identification and characterization of key enzymatic players may suggest new therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of protease M/neurosin in oligodendrocytes and their progenitors in an animal model of multiple sclerosis

Terayama

Bandô

Jiang³

et al. 2005

Neuroscience Letters

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Elsevier, Terayama, Ryuji ; Bando, Yoshio ; Jiang, Ying-Ping ; Mitrovic, Branka ; Yoshida, Shigetaka, Neuroscience Letters, 382(1-2), 2005, 82-87. authorTo determine the possible involvement of protease M/neurosin in demyelinating diseases of the CNS, we examined its expression in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a recognized animal model of multiple sclerosis (MS). In situ hybridization, immunohistochemistry and quantitative real-time polymerase chain reaction (PCR) demonstrated that EAE caused an increase in the expression of protease M/neurosin mRNA and its protein product throughout the white and gray matter surrounding demyelinating lesions. Combined in situ hybridization and immunohistochemistry demonstrated that most of the cells expressing protease M/neurosin mRNA within control spinal cord showed immunoreactivity for CNPase or NG2, cell-specific markers for oligodendrocytes and their progenitors, respectively. In the spinal cord from mice with EAE, the expression of protease M/neurosin mRNA in CNPase-positive cells appeared to be increased while double-labeled cells positive for protease M/neurosin mRNA and NG2 were rarely found in areas associated with demyelinating lesions. Although a prominent accumulation of inflammatory cells including T-cells was observed in the vicinity of demyelinated lesions, these cells were not associated with protease M/neurosin mRNA expression. The levels of protease M/neurosin mRNA expression were unchanged in the spleen and even decreased in the thymus during the course of EAE. These observations suggest that the differential expression of protease M/neurosin in mature oligodendrocytes and their progenitors is involved in the pathogenesis of MS and EAE

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“…For example, tPA mediates activation of microglia, the resident immune cells of the CNS, upon excitotoxic injury in the brain (20). In addition, in brains of MS patients, tPA is particularly associated with inflammatory cells in the perivascular compartment and high tPA activities in the circulation correlate with the disease progression (21)(22)(23). tPA activity is also increased in areas of inflammatory damage in the animal model of MS, experimental autoimmune encephalomyelitis (EAE) (24).…”

mentioning

confidence: 99%

Tissue-Type Plasminogen Activator Is a Regulator of Monocyte Diapedesis through the Brain Endothelial Barrier

Reijerkerk

Kooij

Pol

et al. 2008

The Journal of Immunology

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Inflammatory cell trafficking into the brain complicates several neurological disorders including multiple sclerosis. Normally, reliable brain functioning is maintained and controlled by the blood-brain barrier (BBB), which is essential to restrict the entry of potentially harmful molecules and cells from the blood into the brain. The BBB is a selective barrier formed by dedicated brain endothelial cells and dependent on the presence of intracellular tight junctions. In multiple sclerosis, a severe dysfunction of the BBB is observed, which is key to monocyte infiltration and inflammation in the brain. Proteolytic activity has been associated with these inflammatory processes in the brain. Our studies in plasma of rats indicated that the extracellular protease tissue-type plasminogen activator (tPA) correlates with the clinical signs of experimental allergic encephalomyelitis, a rat model of multiple sclerosis. In this study, we studied the function of the tPA during diapedesis of monocytes through a rat and human brain endothelial barrier. Monocyte-brain endothelial cell coculture experiments showed that monocytes induce the release of tPA by brain endothelial cells, which subsequently activates the signal transduction protein extracellular signal related kinase (ERK1/2), both involved in monocyte diapedesis. Importantly, live imaging and immunoblot analyses of rat brain endothelial cells revealed that tPA and ERK1/2 control the breakdown of the tight junction protein occludin. These studies identify tPA as a novel and relevant pathological mediator of neuroinflammation and provide a potential mechanism for this.

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Tissue plasminogen activator gene expression in multiple sclerosis brain tissue

Cited by 24 publications

References 34 publications

A Role for the Plasminogen Activator System in Inflammation and Neurodegeneration in the Central Nervous System during Experimental Allergic Encephalomyelitis

A Role for the Plasminogen Activator System in Inflammation and Neurodegeneration in the Central Nervous System during Experimental Allergic Encephalomyelitis

Differential expression of protease M/neurosin in oligodendrocytes and their progenitors in an animal model of multiple sclerosis

Tissue-Type Plasminogen Activator Is a Regulator of Monocyte Diapedesis through the Brain Endothelial Barrier

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