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Cerebral Cortex Advance Access published online on September 26, 2009
Cerebral Cortex, doi:10.1093/cercor/bhp193
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

P2Y12 Receptor Protein in Cortical Gray Matter Lesions in Multiple Sclerosis

Susanna Amadio1, Cinzia Montilli1, Roberta Magliozzi2, Giorgio Bernardi1, Richard Reynolds2 and Cinzia Volonté1,3

1 Santa Lucia Foundation, 00143 Rome, Italy, 2 Department of Cellular & Molecular Neuroscience, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, London W12 0NN, 3 Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy

Address correspondence to Susanna Amadio. email: s.amadio{at}hsantalucia.it.

Although Multiple Sclerosis (MS) is regarded as a white matter disease, the incidence of demyelination and axonal injury is prominent also in gray matter. In MS, extracellular adenosine triphosphate (ATP) is an important mediator of central nervous system pathology via its ability to cause oligodendrocyte excitotoxicity. We have analyzed the distribution pattern of all ionotropic P2X and metabotropic P2Y receptors for ATP in postmortem samples of the cerebral cortex from healthy human subjects as well as MS patients. We focus particularly on the P2Y12 subtype that is highly enriched in oligodendrocytes. We correlate the expression of this receptor to the extent of gray matter demyelination and pathological alterations occurring during secondary progressive MS. Using triple immunofluorescence and confocal analysis, we show that in sections of cerebral cortex from postmortem MS brains, the P2Y12 protein is present in myelin and interlaminar astrocytes but absent from protoplasmic astrocytes residing in the deeper cortical layers, from microglia/macrophages, and from intact demyelinated axons. We report that a decreased P2Y12 receptor immunoreactivity in proximity to the lesions is directly correlated with the extent of demyelination found in all types of gray matter cortical plaques (I–III) and subcortical white matter. Our study provides further insights into the pathogenetic features of MS and suggests that the loss of purinergic P2Y12 receptors might be detrimental to tissue integrity.

Key Words: astrocyte • demyelination • extracellular ATP • oligodendrocyte • purinergic receptor


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