Elevated matrix metalloproteinase-9 and degradation of perineuronal nets in cerebrocortical multiple sclerosis plaques.
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.
Gray
Elizabeth
E
MS Laboratories, Burden Centre, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.
Thomas
Taya Louise
TL
Betmouni
Samar
S
Scolding
Neil
N
Love
Seth
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002540:Cerebral Cortex / Q000201:enzymology* / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010320:Parvalbumins / Q000378:metabolism; D037121:Plant Lectins / Q000096:biosynthesis; D034781:Receptors, N-Acetylglucosamine / Q000096:biosynthesis
D010320:Parvalbumins; D037121:Plant Lectins; D034781:Receptors, N-Acetylglucosamine; C040129:wisteria lectin; D020780:Matrix Metalloproteinase 9