Anales RANF

S19-03 THE P2X7 RECEPTOR HAS A SCAVENGER ROLE IN THE CENTRAL NERVOUS SYSTEM WHICH IS LITTLE AFFECTED BY ANTAGONISTS OF P2X7 PORE FUNCTION James S Wiley and Ben J Gu Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria, Australia. Most studies of P2X7 receptors have focused on the some aspect of the proinflammatory ‘pore’ function but the requirement for activation by high concentrations of ATP agonist suggest the receptor has an alternative non-inflammatory function in the CNS. Our group has proposed a major function of P2X7 is to phagocytose apoptotic neurones and debris in the absence of ATP and play a major role in early human neurogenesis which occurs in the non-inflammatory milieu of early life. Demonstration of the innate phagocytic ability of human monocytes or microglia requires the absence of serum proteins since as little as 1-5 % serum (either autologous or heterologous) abolishes all phagocytic function not only by P2X7 but also by other scavenger receptors. This inhibitory action of serum resides in a protein fraction containing copper and/or zinc containing glycoproteins such as ceruloplasmin and amyloid precursor protein. Genetic studies have identified a rare polymorphic haplotype spanning the P2X7-P2X4 gene loci which abolishes the phagocytic ability of the receptor not only in age-related macular degeneration ( a disease of impaired innate phagocytosis) but also in a cohort with primary progressive multiple sclerosis (PPMS, n = 777) with a significant odds ratio of 1.82. A second unique P2X7-P2X4 haplotype has been shown to segregate with MS disease in six closely related members of a Canadian pedigree. This haplotype impairs surface expression of P2X7 receptors to values of only 5% of wild type and in turn nearly abolishes P2X7 mediated phagocytosis. This P2X7- mediated phagocytosis is not or little affected by three different selective P2X7 antagonists which abolish P2X7 pore function. These antagonists have few side effects and blocking neuroinflammation will have beneficial effects by stimulating innate phagocytosis in the brain.