Elevated Matrix Metalloproteinase-9 and Degradation of Perineuronal Nets in Cerebrocortical Multiple Sclerosis Plaques

MS Laboratories, Burden Centre, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 10/2008; 67(9):888-99. DOI: 10.1097/NEN.0b013e318183d003
Source: PubMed


Matrix metalloproteinases (MMPs) degrade extracellular matrix; MMP activity, particularly of MMP-9, is elevated in the white matter in multiple sclerosis (MS) patients. The cerebral cortical extracellular matrix includes perineuronal nets (PNs) that surround parvalbumin-positive neurons (PV-positive neurons) and are important for their function. We measured active and total MMP-9 levels in postmortem homogenates of demyelinated and nondemyelinated cerebral cortical regions from 9MS and 7 control cases and assessed Wisteria floribunda agglutin (WFA)-positive PNs in paraffin sections from 15 MS and 6 controls and PV-positive neurons in sections from 26 MS and 6 controls. Active MMP-9 levels were higher in demyelinated than in nondemyelinated or control cortex (p < 0.05). The area fraction positive for WFA was lower in demyelinated than nondemyelinated MS or control cortex; the latter difference was significant (p < 0.05). Most PV-positive neurons in demyelinated but not intact cortex lackeda PN, and some showed perikaryal phosphorylated neurofilament protein accumulation. Loss of WFA-labeled PNs was not associated with reduced PV-positive neurons numbers. Thus, elevated MMP-9 in cortical plaques is associated with loss of PNs; PV-positive neurons are preserved but show abnormal neurofilament accumulations. Matrix metalloproteinase-mediated degradation of PNs in cortical plaques may, therefore, contribute to neuronal dysfunction and degeneration in MS patients.

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    • "Thus, expression of several metalloproteases may be altered in subjects with SZ as a result of genetic predisposition. Second, PNN integrity and expression of metalloproteases are markedly affected by stress and immune responses (Medina-Flores et al., 2004; Franklin et al., 2008; Gray et al., 2008; Fillman et al., 2014). These responses have been linked to the pathogenesis of SZ, with a very recent study pointing to a genetic contribution to immune factor involvement (Arion et al., 2007; Saetre et al., 2007; Smith et al., 2007; Fillman et al., 2013; Horvath and Mirnics, 2014; Ripke and Schizophrenia Working Group of the Psychiatric Genomics, 2014). "
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    ABSTRACT: Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia. In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex. The formation of these specialized extracellular matrix (ECM) aggregates during postnatal development, their functions, and association with distinct populations of GABAergic interneurons, bear great relevance to the pathophysiology of schizophrenia. PNNs gradually mature in an experience-dependent manner during late stages of postnatal development, overlapping with the prodromal period/age of onset of schizophrenia. Throughout adulthood, PNNs regulate neuronal properties, including synaptic remodeling, cell membrane compartmentalization and subsequent regulation of glutamate receptors and calcium channels, and susceptibility to oxidative stress. With the present paper, we discuss evidence for PNN abnormalities in schizophrenia, the potential functional impact of such abnormalities on inhibitory circuits and, in turn, cognitive and emotion processing. We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors. Notably, the composition of PNNs is regulated dynamically in response to factors such as fear, reward, stress, and immune response. This regulation occurs through families of matrix metalloproteinases that cleave ECM components, altering their functions and affecting plasticity. Several metalloproteinases have been proposed as vulnerability factors for schizophrenia. We speculate that the physiological process of PNN remodeling may be disrupted in schizophrenia as a result of interactions between matrix remodeling processes and immune system dysregulation. In turn, these mechanisms may contribute to the dysfunction of GABAergic neurons.
    Full-text · Article · Jan 2015 · Schizophrenia Research
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    • "Enhanced lectican expression in the proinflamatory milieu of expanding lesion edges and lectican decreases in plaque centre may influence the failure to support neurite outgrowth axonal regeneration and remyelination (Sobel and Ahmed 2001). Latest studies indicate that in cerebral cortical regions affected by multiple sclerosis the loss of WFA-positive PNs was due to the elevation of metalloproteinase 9 (MMP-9, enzyme that degrade extracellular matrix) and to impairments of PV-positive cells resulting from the accumulation of phosphorylated neurofilament protein (Gray et al. 2008). "
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    ABSTRACT: Perineuronal nets represent well-organised components of the extracellular matrix, which are surrounding cell bodies, dendrites, and axon segments of a particular class of neurones as well as forming lattice-like structures. The role of perineuronal nets is not fully elucidated yet. Perineuronal nets may play a beneficial role by stabilizing the extracellular milieu assuring the characteristic features of enveloped neurons and protecting them from the influence of harmful agents. On the other hand, perineuronal nets create a barrier which limits neuronal plasticity and counteracts regeneration. This review examines recent evidence concerning the significance of the occurrence of perineuronal nets.
    Full-text · Article · Jan 2009 · Acta neurobiologiae experimentalis
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    ABSTRACT: Multiple sclerosis (MS) is characterized by focal demyelinating lesions in white matter (WM) and grey matter (GM) of the central nervous system. Results of studies using quantitative magnetic resonance imaging techniques indicate that GM MS pathology has a significant impact on clinical symptoms and disability in MS, and may occur partly independently of WM pathology. Subpial cerebral and cerebellar cortexes are predilection sites for demyelination in MS. Significant neuronal and axonal pathology has been detected in GM MS lesions. The pathology of MS lesions is location-dependent; there is less pronounced inflammation in GM lesion areas than in WM lesions. The presence and extent of GM lesions has recently been correlated to meningeal inflammation, and cells infected with the Epstein-Barr virus have been detected in meningeal infiltrates, suggesting a role of meningeal inflammation in cortical lesion pathogenesis.
    No preview · Article · Aug 2009 · Acta neurologica Scandinavica. Supplementum
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