P2Y12 Receptor Protein in Cortical Gray Matter Lesions in Multiple Sclerosis

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.

Pathophysiology of astroglial purinergic signalling

“…These studies suggest that signalling via the P2X 7 R may modulate the astrocytic response to inflammation [237]. An immunofluorescence and confocal analysis in sections of cerebral cortex from postmortem MS brain indicated that P2Y 12 protein is present in myelin and in interlaminar astrocytes; P2Y 12 Rs were also highly enriched in oligodendrocytes [238].…”

P2Y12Receptor on the Verge of a Neuroinflammatory Breakdown

“…Cryostat sections (30–40  μ m thick) were either stained with Luxol fast blue and cresyl fast violet (Kluver-Barrera staining), in order to detect white matter lesions and their cellularity, or subjected to immunohistochemistry for MBP, in order to distinguish grey matter lesions. Sections were processed in free-floating for double immunofluorescence studies, as described in Amadio and collaborators [13]. …”

P2Y12 receptors in platelets and other hematopoietic and non-hematopoietic cells

“…The presence of this receptor has been established in oligodendrocytes and myelin sheaths of rat cerebral cortex, subcortical areas, and periventricular white matter [141]. A recent post mortem study of cerebral cortex from patients with multiple sclerosis found a strong correlation between the extent of lesions and decreased expression of the P2Y 12 receptor at the axon-myelin interface [142] suggesting that loss of P2Y 12 receptor expression might be detrimental to tissue integrity. Whether this decreased expression is the cause or the consequence of the disease is not established.…”