Elevated matrix metalloproteinase-9 and degradation of perineuronal nets in cerebrocortical multiple sclerosis plaques
Abstract
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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Altered MMP and ADAMTS expression is associated with PNN reduction.
“Notably, altered expression of MMPs and ADAMTS was found to be associated with PNN reduction (Gray et al., 2008).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Gray et al., 2008
Stress and immune responses markedly affect PNN integrity and metalloprotease expression.
“Second, PNN integrity and expression of metalloproteases are markedly affected by stress and immune responses (Fillman et al., 2014; Franklin et al., 2008; Gray et al., 2008; Medina-Flores et al., 2004).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Gray et al., 2008
PNN degradation occurs in multiple sclerosis.
“For example, degradation of the PNN is a feature of multiple sclerosis (Gray et al., 2008)”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Gray et al., 2008
PNN degradation in multiple sclerosis has been attributed to MMP production by cytokines or activated microglia.
“The degradation of the PNN in multiple sclerosis has been attributed to the production of MMPs by cytokines or activated microglia (Gray et al., 2008).”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Gray et al., 2008
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- Authors
- Gray, E., Thomas, T. L., Betmouni, S., Scolding, N., & Love, S.
- Affiliations
- Frenchay Hospital (GB)
- Corresponding author
- Gray, Elizabeth
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-09
- Volume
- 67
- Issue
- 9
- Pages
- 888-899
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W2044790277
- Cited by
- 51
- References
- 65
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 7 · 2022: 6 · 2021: 4 · 2020: 7 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 4 · 2014: 1 · 2013: 3 · 2012: 1
- FWCI
- 0.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion)
- Funders
- Multiple Sclerosis Society
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- MMP-9, perineuronal nets, multiple sclerosis, demyelination, parvalbumin-positive neurons, extracellular matrix degradation, neurofilament phosphorylation, Wisteria floribunda agglutinin, neuronal dysfunction, postmortem brain
- MeSH terms
- Adult, Aged, Aged, 80 and over, Cerebral Cortex, Extracellular Matrix, Female, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Male, Middle Aged, Multiple Sclerosis, Neurons, Parvalbumins, Matrix Metalloproteinase 9, Receptors, N-Acetylglucosamine, Plant Lectins
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