Anales RANF

S9-04 ADENOSINE A 2A RECEPTOR ACTIVATION ATTENUATE NMDA RECEPTOR FUNCTION IN ALZHEIMER DISEASE Gemma Navarro 1,2 , David Aguinaga 2,3 , Irene Reyes 2,3 , Iu Raïch 2,3 , Alejandro Lillo 1,2 , Anna Del Ser-Badia 4 , Carlos A. Saura 4 , Rafael Franco 2,3 . 1 University of Barcelona, Barcelona, Spain , 2 Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) .Instituto de Salud Carlos III. Madrid. Spain, 3 University of Barcelona, Barcelona, Spain , 4 University of Barcelona, IDIBAPS, Barcelona, Spain Alzheimer disease is a neurodegenerative disorder of the central nervous system that manifests with memory, thinking and behavior deterioration. Symptoms usually develop slowly and get worse day after day, until patients are so severe that they interfere with daily tasks. Unfortunately, to date there is no curative or palliative treatment for this disease, only symptomatic interventions. Therefore, new strategies and treatments are required to treat this progressive neurodegenerative pathology. Adenosine receptors play an important role in cognitive function. Adenosine receptors are divided in high affinity receptors: containing A1R and A2AR and low affinity receptors: containing A2B and A3. Interestingly, it has been observed that caffeine improve cognitive function in AD patients. And that antagonists of adenosine A2A receptors mimic the beneficial effects of caffeine on cognitive function. Also, it has been described that A2AR antagonist prevent amiloid- β neurotoxic effects. On the other hand, NMDA receptors are implicated in the control of memory and learning, being one of the most analyzed targets for Alzheimer disease. However, is still deficient the demonstration of the mechanism underlying NMDA receptor role in AD. Since nineties, it has been demonstrated that GPCR can interact forming oligomeric complexes that acquire new properties. We here provide data that demonstrate in transfected HEK-293T cells that NMDA receptors interact with adenosine A2A receptors. Moreover, A2AR stimulation block NMDA signaling in MAPK phosphorylation and calcium relase. Moreover, A2AR couple to Gs protein, thus analyzing cAMP accumulation it has been observed that NMDA stimulation also block A2AR activity. Finally, the A2A-NMDA receptor complex has been identified in hippocampus neuronal primary cultures, showing an important increase in APP Sw,Ind animal model in comparison with controls. It has been observed that in neuronal cells, A2AR agonists induce an important decrease in NMDA signaling. Due to the increased expression of A2AR in neuroinflation conditions, NMDA signaling in APP Sw,Ind animal model is completely blocked by A2AR stimulation. All together, we offer a new mechanism demonstrating a functional and structural regulation of adenosine A2A receptor over NMDAR in Alzheimer disease. Acknowledgements: Supported by a CIBERNED intramural collaborative grant and by grant AARFD-17-503612 from the U.S. Alzheimer’s Association.