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Updated: Jun 20, 2026
Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
P2Y12 receptor protein in cortical gray matter lesions in multiple sclerosis
Susanna Amadio1, Cinzia Montilli, Roberta Magliozzi
1Santa Lucia Foundation, Rome, Italy. s.amadio@hsantalucia.it
Abstract:
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 P2Y(12) 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 P2Y(12) 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 P2Y(12) 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 P2Y(12) receptors might be detrimental to tissue integrity.
Insights
In multiple sclerosis (MS) gray matter, the P2Y12 receptor, crucial for oligodendrocytes, decreases near lesions. This loss correlates with demyelination, suggesting a role in MS pathology.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Multiple Sclerosis (MS) pathology affects both white and gray matter, involving demyelination and axonal injury.
- Extracellular adenosine triphosphate (ATP) mediates central nervous system pathology in MS, particularly oligodendrocyte excitotoxicity.
- Purinergic receptors (P2X and P2Y) are key mediators of ATP signaling in the central nervous system.
Purpose of the Study:
- To analyze the distribution of ATP receptors (P2X and P2Y) in the cerebral cortex of healthy and MS patients.
- To investigate the role of the P2Y12 receptor, enriched in oligodendrocytes, in gray matter demyelination in secondary progressive MS.
- To correlate P2Y12 receptor expression with the extent of gray matter demyelination and pathological alterations in MS.
Main Methods:
- Analysis of postmortem cerebral cortex samples from healthy and MS patients.
- Triple immunofluorescence and confocal microscopy to visualize P2Y12 receptor protein distribution.
- Correlation analysis between P2Y12 receptor immunoreactivity and demyelination extent in cortical plaques and subcortical white matter.
Main Results:
- P2Y12 protein was found in myelin and interlaminar astrocytes but not in protoplasmic astrocytes, microglia/macrophages, or intact demyelinated axons in MS gray matter.
- Decreased P2Y12 receptor immunoreactivity near lesions directly correlated with the extent of demyelination in gray matter cortical plaques (I-III) and subcortical white matter.
- The P2Y12 receptor is specifically localized in oligodendrocytes and associated myelin structures within the gray matter.
Conclusions:
- The study reveals specific localization patterns of P2Y12 receptors in the cerebral cortex relevant to MS pathology.
- Loss of P2Y12 receptor expression is associated with gray matter demyelination in progressive MS.
- Reduced P2Y12 receptor levels may contribute to tissue damage and impaired repair in MS, highlighting its potential as a therapeutic target.
