Differences in expression of junctional adhesion molecule-A and β-catenin in multiple sclerosis brain tissue: increasing evidence for the role of tight junction pathology

Padden, Maureen; Leech, Suzie; Craig, Beverly; Kirk, John M.; Brankin, Brenda; McQuaid, Stephen

doi:10.1007/s00401-006-0145-x

Cited by 70 publications

(49 citation statements)

References 62 publications

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“…Nevertheless, FGF-2 upregulation in perivascular astrocytes was observed selectively within the NAGM of MS patients in close association with a slightly disrupted tight junction profile, probably mediated by an inflammatory environment (Kinter et al, 2009). Although the tight junction profile within the white matter is disrupted in all types of lesions (Claudio et al, 1995;Kirk et al, 2003;Padden et al, 2007), it remains unclear why tight junctions within the gray matter are not altered to the same degree. While it is accepted as a regulator of the vascular tone (Zhou et al, 1998), the relevance of FGF-2 in inducing and maintaining BBB integrity has been shown by different in vitro approaches.…”

Section: Discussionmentioning

confidence: 99%

“…The gray matter of blocks from the cerebral cortex of controls, where FGF-2 ϩ astrocytes were absent, showed an unaltered ZO-1 profile ( Fig. 3G-I), an indicator of BBB-associated tight junction integrity in MS (Kirk et al, 2003;Padden et al, 2007). In contrast, FGF-2 ϩ perivascular astrocytes were invariably associated with a slightly discontinuous tight junction profile (Fig.…”

Section: Fgf-2 Is Differentially Upregulated In Ms Patientsmentioning

confidence: 96%

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FGF-2 and Anosmin-1 Are Selectively Expressed in Different Types of Multiple Sclerosis Lesions

Clemente

Ortega²,

Arenzana³

et al. 2011

J. Neurosci.

114

148

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Multiple sclerosis is a demyelinating disease that affects ϳ2,000,000 people worldwide. In the advanced stages of the disease, endogenous oligodendrocyte precursors cannot colonize the lesions or differentiate into myelinating oligodendrocytes. During development, both FGF-2 and Anosmin-1 participate in oligodendrocyte precursor cell migration, acting via the FGF receptor 1 (FGFR1). Hence, we performed a histopathological and molecular analysis of these developmental modulators in postmortem tissue blocks from multiple sclerosis patients. Accordingly, we demonstrate that the distribution of FGF-2 and Anosmin-1 varies between the different types of multiple sclerosis lesions: FGF-2 is expressed only within active lesions and in the periplaque of chronic lesions, whereas Anosmin-1 is upregulated within chronic lesions and is totally absent in active lesions. We show that the endogenous oligodendrocyte precursor cells recruited toward chronic-active lesions express FGFR1, possibly in response to the FGF-2 produced by microglial cells in the periplaque. Also in human tissue, FGF-2 is upregulated in perivascular astrocytes in regions of the normal-appearing gray matter, where the integrity of the blood-brain barrier is compromised. In culture, FGF-2 and Anosmin-1 influence adult mouse oligodendrocyte precursor cell migration in the same manner as at embryonic stages, providing an explanation for the histopathological observations: FGF-2 attracts/ enhances its migration, which is hindered by Anosmin-1. We propose that FGF-2 and Anosmin-1 are markers for the histopathological type and the level of inflammation of multiple sclerosis lesions, and that they may serve as novel pharmacogenetic targets to design future therapies that favor effective remyelination and protect the blood-brain barrier.

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Section: Discussionmentioning

confidence: 99%

Section: Fgf-2 Is Differentially Upregulated In Ms Patientsmentioning

confidence: 96%

FGF-2 and Anosmin-1 Are Selectively Expressed in Different Types of Multiple Sclerosis Lesions

Clemente

Ortega²,

Arenzana³

et al. 2011

J. Neurosci.

114

148

View full text Add to dashboard Cite

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“…Negative controls were samples that underwent same staining procedure with the exclusion of the primary antibodies. Cortex of the frontal part of the normal brain [13], as well as normal skin, served as positive controls. The analysis of the labeling was performed by two independent observers, i.e.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Changes of AXIN-1 and Beta-Catenin in Neuroepithelial Brain Tumors

Martić

Pećina‐Šlaus

Kušec

et al. 2009

Pathol. Oncol. Res.

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In the present study changes of components of Wnt signaling pathway--axin (AXIN1) and beta-catenin (CTNNB1) in a sample of 72 neuroepithelial brain tumors were investigated. AXIN-1 gene was tested by PCR/loss of heterozygosity (LOH). Immunostaining and image analysis revealed the quantity and localization of relevant proteins. Polymorphic marker for AXIN-1, showed LOH in 11.1% of tumors. LOH was distributed to 6.3% of glioblastomas, one was found in neuroepithelial dysembrioplastic tumor and one in medulloblastoma. Down regulation of axin expression and up regulation of beta-catenin were detected in the analyzed tumors. Axin was observed in the cytoplasm in 68.8% of samples, in 28.1% in both the cytoplasm and nucleus and 3.1% had no expression. Beta-catenin was observed mainly in the nucleus and cytoplasm (59.4%). Expression in 34.4% of samples was in the cytoplasm and 6.3% showed no expression. Comparison of mean values of relative increase of axin and beta-catenin showed that they are significantly reversely proportional (P = 0.014). Relative quantity of beta-catenin in patients with gross deletion of AXIN1 was significantly higher in comparison to patients without LOH (P = 0.040). Our results demonstrate that changes of key components of the Wnt signaling play a role in neuroepithelial brain tumors.

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“…Disruption of endothelial adherens junctions (AJs) within active MS lesions releases β-catenin from the plasma membrane (36) and results in transcriptional activity (37,38). Moreover, Wnt3a and -5a are expressed in the dorsal spinal cord during EAE (39), and both T-cell factor 4 (Tcf4) and adenomatosis polyposis coli downregulated 1 (Apcdd1), a transcriptional downstream Wnt target (40,41), are expressed in subsets of oligodendrocytes in active MS/EAE lesions (42)(43)(44)(45).…”

mentioning

confidence: 99%

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Lengfeld

Lutz

Smith

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

133

127

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Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/ β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4 + T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.blood-brain barrier | endothelial cell | Wnt/β-catenin signaling | MS | EAE I n both multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), leukocytes infiltrate the central nervous system (CNS) across a damaged blood-brain barrier (BBB) to mediate myelin destruction and neuronal damage (1). BBB breakdown is a contributing factor to the pathogenesis of both MS and EAE (2-4). Structural and functional BBB degradation precedes lesion development in both MS and EAE (5-9), and focal BBB abnormalities correlate with clinical exacerbations in the relapsing-remitting form of MS (10). Moreover, BBB leakage precedes the entry of T cells and monocytes into the brain parenchyma (7, 11) and coincides with early infiltration of neutrophils before the onset of EAE (12). Although the severity of barrier leakage decreases over time for most relapsing-remitting MS lesions, as assessed by gadoliniumenhancing magnetic resonance imaging (7, 13-15), whether BBB recovery is an active process and, if so, which pathways mediate its repair, remain unclear.The BBB achieves its highly selective permeability through the presence of (i) tight junctions (TJs) that prevent paracellular diffusion of small molecules and immune cells between endothelial cells (ECs), (ii) very few endocytotic vesicles that restrict movement of large mo...

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Differences in expression of junctional adhesion molecule-A and β-catenin in multiple sclerosis brain tissue: increasing evidence for the role of tight junction pathology

Cited by 70 publications

References 62 publications

FGF-2 and Anosmin-1 Are Selectively Expressed in Different Types of Multiple Sclerosis Lesions

FGF-2 and Anosmin-1 Are Selectively Expressed in Different Types of Multiple Sclerosis Lesions

Changes of AXIN-1 and Beta-Catenin in Neuroepithelial Brain Tumors

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

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