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Elevated matrix metalloproteinase-9 and degradation of perineuronal nets in cerebrocortical multiple sclerosis

Elizabeth Gray1, Taya Louise Thomas, Samar Betmouni

  • 1MS Laboratories, Burden Centre, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.

Journal of Neuropathology and Experimental Neurology
|August 22, 2008
PubMed

Insights

Elevated matrix metalloproteinase-9 (MMP-9) in multiple sclerosis (MS) brains degrades perineuronal nets (PNs) surrounding neurons. This MMP-9 activity leads to PN loss in cortical lesions, potentially causing neuronal dysfunction in MS patients.

Area of Science:

  • Neuroscience
  • Pathology
  • Biochemistry

Background:

  • Matrix metalloproteinases (MMPs), particularly MMP-9, are implicated in multiple sclerosis (MS) pathogenesis.
  • Extracellular matrix components, including perineuronal nets (PNs), are crucial for neuronal function in the cerebral cortex.
  • PNs ensheath parvalbumin-positive (PV) neurons, playing a vital role in regulating neuronal activity.

Purpose of the Study:

  • To investigate the relationship between elevated MMP-9 activity and the integrity of PNs in the cerebral cortex of MS patients.
  • To assess the impact of MMP-9 on PV-positive neurons and their surrounding PNs in demyelinated lesions.

Main Methods:

  • Quantification of active and total MMP-9 levels in postmortem cortical tissue from MS and control cases.
  • Assessment of Wisteria floribunda agglutinin (WFA)-positive PNs and PV-positive neurons in MS and control cortical sections.
  • Histological analysis of demyelinated and non-demyelinated cortical regions.

Main Results:

  • Active MMP-9 levels were significantly higher in demyelinated cortical regions compared to non-demyelinated or control cortex.
  • A significant reduction in WFA-labeled PNs was observed in demyelinated MS cortical areas.
  • While PV-positive neuron numbers were preserved, most neurons in demyelinated areas lacked PNs and some exhibited neurofilament accumulation.

Conclusions:

  • Elevated MMP-9 in MS cortical plaques contributes to the degradation and loss of PNs.
  • The loss of PNs, rather than neuron loss, may be a key factor in neuronal dysfunction in MS cortical lesions.
  • Matrix metalloproteinase-mediated PN degradation is a potential mechanism underlying neuronal dysfunction and degeneration in multiple sclerosis.

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