Co-localization of hyaluronic acid and chondroitin sulfate proteoglycan in rat cerebral cortex

doi:10.1016/0006-8993(92)90759-3

Brain Research

Volume 579, Issue 1, 1 May 1992, Pages 173-177

https://doi.org/10.1016/0006-8993(92)90759-3 Get rights and content

Abstract

The distribution of hyaluronate (HA) and chondroitin sulfate (CS) proteoglycan in the rat cerebral cortex was compared. For the localization of HA, the sections were incubated with human glial hyaluronate-binding protein (GHAP) and then reacted with monoclonal or polyclonal antibodies to GHAP. Polyclonal antibodies raised in rabbit were used for double-labeling experiments with monoclonal antibodies raised in mice and reacting with CS proteoglycans. Little reactivity was observed in rat cerebral cortex with polyclonal GHAP antibodies if the sections were not incubated with GHAP. Monoclonal antibodies to GHAP did not react with murine tissues. CS proteoglycans were localized in chondroitinase-digested sections with monoclonal antibodies reacting with the 4-sulfated oligosaccharide stubs formed by the digestion with chondroitinase ABC of CS side chains. In the rat cerebral cortex, the distribution of CS proteoglycans was similar to that reported by Bertolotto, A., Rocca, G. and Schiffer, D.,J. Neurol. Sci., 100 (1990) 113–123, and his collaborators using the same antibodies. Many neurons mainly located in the upper and deep cortical layers were surrounded by CS immunoreactive material. Several (but not all) CS-positive neurons also stained for HA with an identical distribution except that in most instances the staining was confined to the periphery of the perikaryon and did not extend to the dendritic tree. The finding suggests that cerebral cortex CS proteoglycan is capable of interacting with HA.

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PGs are capable of binding hyaluronan and because of this ability they serve as organizational scaffolds within the matrix (Fig. 2). PGs have roles in numerous cellular processes including cell adhesion, receptor binding, growth, migration, barrier formation, and interaction with other ECM molecules (for review see, Ruoslahti, 1996; Bignami et al., 1992; Rhodes and Fawcett, 2004). PGs are composed of a protein core with GAG side chains; the length and number of side chains can vary, contributing to the diversity of PGs. Each GAG chain is composed of two alternating monosaccharide units – uronic acid and either N-acetylgalactosamine or N-acetylglucosamine.
During development the extracellular matrix (ECM) of the central nervous system (CNS) facilitates proliferation, migration, and synaptogenesis. In the mature nervous system due to changes in the ECM it provides structural stability and impedes proliferation, migration, and synaptogensis. The perineuronal net (PN) is a specialized ECM structure found primarily surrounding inhibitory interneurons where it forms a mesh-like structure around points of synaptic contact. The PN organizes the extracellular space by binding multiple components of the ECM and bringing them into close proximity to the cell membrane, forming dense aggregates surrounding synapses. The PN is expressed late in postnatal development when the nervous system is in the final stages of maturation and the critical periods are closing. Once fully expressed the PN envelopes synapses and leads to decreased plasticity and increases synaptic stability in the CNS. Disruptions in the PN have been studied in a number of disease states including epilepsy. Epilepsy is one of the most common neurologic disorders characterized by excessive neuronal activity which results in recurrent spontaneous seizures. A shift in the delicate balance between excitation and inhibition is believed to be one of the underlying mechanisms in the development of epilepsy. During epileptogenesis, the brain undergoes numerous changes including synaptic rearrangement and axonal sprouting, which require structural plasticity. Because of the PNs location around inhibitory cells and its role in limiting plasticity, the PN is an important candidate for altering the progression of epilepsy. In this review, an overview of the ECM and PN in the CNS will be presented with special emphasis on potential roles in epileptogenesis.
Localization and developmental expression patterns of CSPG-cs56 (aggrecan) in normal and dystrophic retinas in two rat strains
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However, Koga et al. (2003) showed that HA and heparan sulfate were found in the NFL, IPL and OPL between P1 and P14, but not after P21. HA was faintly observed in the OS by P7, and gradually increased up to P49 (similar to chondroitin sulfate: for cortex see also Bignami et al., 1992). Inatani et al. (1999b) reported that neurocan (a 378 bp CNS-specific proteoglycan) in Wistar rat retinas was most conspicuous in the IPL and moderately expressed in the OPL, reaching peak levels between P7 and P14, which then fall to very low levels by P42.
Proteoglycans have a number of important functions in the central nervous system. Aggrecan (hyaluronan-binding proteoglycan, CSPG-cs56) is found in the extracellular matrix of cartilage as well as in the developing brain. We compared the postnatal distribution of CSPG-cs56 in Long Evans (LE) and Royal College of Surgeons (RCS) rat retinas to determine if this proteoglycan played a role in the development of dystrophic retinas. CSPG-cs56 expression was examined in rat retinas aged between birth (postnatal day 0, P0) and P150 using immunofluorescence and Western-blots. Immunofluorescence was quantified using ImageJ. GFAP staining was used to compare Müller cell labeling and the distribution of CSPG-cs56. Both rat strains showed a significant rise in total retinal CSPG-cs56 between P0 and P21; values peaked on P21 in LE rats and P14 in RCS rats. CSPG-cs56 then significantly decreased to lower levels (P35) in both strains before reaching significantly higher levels by P90–P150. CSPG-cs56 positive staining was present in the ganglion cell layer at birth and clear layering of the inner plexiform layer was seen between P7 and P21 due to dendritic staining of retinal ganglion cells. Staining was less intense and diffuse within the outer plexiform over a similar time-course. Light CSPG-cs56 labeling in the region of the outer segments was present at (P14) and became more intense as the retina approached maturity. CSPG-cs56 in the outer segments was the main contributor to the higher expression in older animals. Substantial differences in CSPG-cs56 labeling were not seen between LE and RCS rats. There was no evidence to suggest that Müller cells were the source of CSPG-cs56 in either rat strain, although their staining distributions had a degree of overlap. The lack of significant differences between LE and RCS rats indicates that CSPG-cs56 may not be involved in the degenerative process or the reorganization of the RCS rat retina. We suggest that the main role of CPSG-cs56 is to maintain retinal ganglion cell dendritic structure in the inner plexiform layer and is closely related to providing adequate support and flexibility for the photoreceptor outer segments, which is necessary to maintain their function.
Aggrecan-based extracellular matrix shows unique cortical features and conserved subcortical principles of mammalian brain organization in the Madagascan lesser hedgehog tenrec (Echinops telfairi Martin, 1838)
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Clear differences also occurred in connected subnuclei, such as the motor trigeminal nucleus and the paratrigeminal nucleus (Fig. 6B, C). Hyaluronan is shown to be an ubiquitous glycosaminoglycan component (Delpech et al., 1989; Bignami et al., 1992; Yasuhara et al., 1994) present in PNs and neuropil zones as well as at large nodes of Ranvier (Fig. 6D, E); however, there are regional pattern displayed by B-HABP staining, as shown for the motor trigeminal nucleus (Fig. 6D, E). The results of the present study show that the extracellular matrix is an integral part of the unique brain architecture of the Madagascan lesser hedgehog tenrec.
The Madagascan tenrecs (Afrotheria), an ancient mammalian clade, are characterized by unique brain anatomy. Striking features are an expanded paleocortex but a small and poorly differentiated neocortex devoid of a distinct granular layer IV. To investigate the organization of cortical areas we analyzed extracellular matrix components in perineuronal nets (PNs) using antibodies to aggrecan, lectin staining and hyaluronan-binding protein. Selected subcortical regions were studied to correlate the cortical patterns with features in evolutionary conserved systems. In the neocortex, paleocortex and hippocampus PNs were associated with nonpyramidal neurons. Quantitative analysis in the cerebral cortex revealed area-specific proportions and laminar distribution patterns of neurons ensheathed by PNs. Cortical PNs showed divergent structural phenotypes. Diffuse PNs forming a cotton wool-like perisomatic rim were characteristic of the paleocortex. These PNs were associated with a dense pericellular plexus of calretinin-immunoreactive fibres. Clearly contoured PNs were devoid of a calretinin-positive plexus and predominated in the neocortex and hippocampus. The organization of the extracellular matrix in subcortical nuclei followed the widely distributed mammalian type. We conclude that molecular properties of the aggrecan-based extracellular matrix are conserved during evolution of mammals; however, the matrix scaffold is adapted to specific wiring patterns of cortical and subcortical neuronal networks.
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Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy characterised by accumulation of resistant prion protein (PrP^BSE), neuronal loss, spongiosus and glial cell proliferation. In this study, properties of the extracellular matrix (ECM) were investigated in boTg110 transgenic mice over-expressing the bovine cellular prion protein (PrP^c) and infected with BSE. Using immunohistochemistry with Wisteria floribunda agglutinin as a specific marker for perineuronal nets (PNNs) and antibodies against aggrecan and hyaluronic acid binding protein, loss of ECM was correlated with PrP^BSE accumulation and activation of astrocytes and microglia. PrP^BSE accumulation and glial cell activation were detected from the earliest stages of the disease and increased in the terminal stages. Decreases in PNNs, aggrecan and hyaluronic acid were observed only in the terminal stages and correlated with the distribution of PrP^BSE and activated glial cells. This study suggests that the loss of PNNs, aggrecan and hyaluronic acid is a consequence of PrP^BSE accumulation. Degradation of ECM in BSE may be due to secretion of degradative enzymes by activated glial cells.
Multiple expression of matrix metalloproteinases in murine neurocysticercosis: Implications for leukocyte migration through multiple central nervous system barriers
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Immune cells coming from subependymal pial vessels expressed multiple active MMPs using both substrates when they were sub-adjacent to the ependyma or traversing it. The composition of the subependyma basal lamina opposing leptomeninges remains to be fully investigated, but in contrast with the pial vessel basal lamina, hyaluronic acid is not detected (Bignami et al., 1992). In addition, in normal mice the expression of tight junction proteins such as claudin-1, -3 and -5 is not detected in ependyma (Alvarez and Teale, 2007a) indicating that the barrier properties of this structure are less restrictive compared with CNS vessels.
During the course of murine neurocysticercosis (NCC), disruption of the unique protective barriers in the central nervous system (CNS) is evidenced by extravasation of leukocytes. This process varies according to the anatomical sites and diverse vascular beds analyzed. To examine mechanisms involved in the observed differences, the expression and activity of eight matrix metalloproteinases (MMPs) were analyzed in a murine model of NCC. The mRNA expression of the MMPs studied was upregulated as a result of infection, and active MMPs were mainly detected in leukocytes migrating into the brain. Polarized expression and gelatinolytic activity of several MMPs were identified in immune cells extravasating pial vessels as early as 1 day post infection. In contrast, leukocytes expressing active MMPs and extravasating parenchymal vessels were not observed until 5 weeks post infection. In ventricular areas, most of the MMP activity was detected in leukocytes traversing the ependyma from leptomeningeal infiltrates. In addition, immune cells continued to express active MMPs after exiting vessels suggesting that enzymatic activity of MMPs is not just required for diapedesis. These results correlate with our previous studies showing differential kinetics in the disruption of the CNS barriers upon infection and help document the important role of MMPs during leukocyte infiltration and inflammation.
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2007, Experimental Neurology
A number of recent studies have established that the bacterial enzyme chondroitinase ABC promotes functional recovery in the injured CNS. The issue of how it works is rarely addressed, however. The effects of the enzyme are presumed to be due to the degradation of inhibitory chondroitin sulphate GAG chains. Here we review what is known about the composition, structure and distribution of the extracellular matrix in the CNS, and how it changes in response to injury. We summarize the data pertaining to the ability of chondroitinase to promote functional recovery, both in the context of axon regeneration and the reactivation of plasticity. We also present preliminary data on the persistence of the effects of the enzyme in vivo, and its hyaluronan-degrading activity in CNS homogenates in vitro. We then consider precisely how the enzyme might influence functional recovery in the CNS. The ability of chondroitinase to degrade hyaluronan is likely to result in greater matrix disruption than the degradation of chondroitin sulphate alone.

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: Supported by NIH Grant NS 13034 and by the Department of Veterans Affairs.

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Co-localization of hyaluronic acid and chondroitin sulfate proteoglycan in rat cerebral cortex

Abstract

Exp. Cell Res.

J. Neurol. Sci.

Brain Res. Bull.

J. Biol. Chem.

Neuroscience

J. Biol. Chem.