Anales RANF

S3-04 PURINERGIC SIGNALING SHAPES MICROGLIAL FUNCTIONS IN ALZHEIMER’S DISEASE Matthias Brückner 1 , Jan N. Hansen 1,2 , Sangyong Lee 3 , Nicole Reichenbach 2 , Gabor C. Petzold 2 , Christa E. Müller 3 and Annett Halle 1,2 1 Center of Advanced European Studies and Research (caesar), Bonn, Germany; 2 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; 3 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Germany. Genome-wide association studies have highlighted the importance of microglia, the main immune cells of the CNS, in Alzheimer's disease (AD), implicating microglia as a promising target for AD treatment. Microglia in mouse models of AD show signs of functional impairment. Whether alterations in purinergic signaling, which under physiological conditions is critically involved in shaping microglial functions, contribute to this phenomenon and whether microglial dysfunction is reversible by targeting purinergic signaling has remained unclear. Plaque-related microglia from APP/PS1 mice showed impaired phagocytic capacity and cell motility in intravital 2-photon microscopy and acute cerebral slice phagocytosis assays. Transcriptional analysis of microglial cells harvested by laser-microdissection revealed significantly altered expression of ectonucleotidases and purinoreceptors in plaque-associated cells. Importantly, short-term treatment of microglia with purinoreceptor agonists or pharmacological blockage of ectonucleotidases rapidly normalized phagocytic and dynamic function of plaque-associated microglia in acute cerebral slices from APP/PS1 mice, suggesting that microglial dysfunction indeed is reversible upon targeting purinergic signaling. In summary, we have identified altered purinergic signaling as a potential cause for the impairment of microglial dynamics, morphology and phagocytic capacity of plaque- associated microglia in the APP/PS1 model and targeting microglial purinergic signaling may represent a promising novel approach for the treatment of AD.