Anales RANF

S14-03 INVOLVEMENT OF P2X7 RECEPTOR ON THE ALZHEIMER DISEASE PROGRESSION, THERAPEUTIC IMPLICATIONS Miguel Diaz-Hernandez 1,2 , Caterina DiLauro 1,2 , Laura de-Diego 1,2,3 , Alvaro Sebastian- Serrano 1,2,4 and Carlos Martinez-Frailes 1,2 1 Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Madrid, Spain; 2 Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain, 3 Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland; 4 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain. Alzheimer disease is a neurodegenerative disease characterized by the presence of senile plaques composed of amyloid- β (Ab) peptide, neurofibrillary tangles formed by hyperphosphorylated tau protein, neuronal loss, and neuroinflammation. Previous works from our group revealed that extracellular ATP, through its selective receptor P2X7 (P2X7R), promotes to the amyloidogenic processing of amyloid precursor protein (APP) via glycogen synthase kinase-3 (GSK3), favoring on this way the neuroinflammation and neurotoxicity induced by Ab. Other groups have also reported that P2X7R is upregulated on microglial cells around the senile plaques. This upregulation progressively rises with age and is parallel with an accumulation of senile plaques and correlates with the synaptic toxicity detected both in animal models reproducing AD and human patients of AD. Furthermore, the late onset of the first AD- associated symptoms suggests that aging associated-changes may be relevant to the disease progression. Since, microglia motility and its capacity to respond to exogenous ATP stimulus decrease with aging, we decided to evaluate whether the P2X7R age related-changes on microglia cells may also be relevant to AD progression. Our results indicate that neuroinflammation induced by Ab peptide causes changes in the P2X7R distribution pattern, increasing its expression in microglial cells at advanced and late stages, when microgliosis occurs, but not in the early stages, in the absence of microgliosis. Besides, we found that P2X7R activation promotes microglial cells migration to senile plaques but decreases their phagocytic capacity. We also found a significant reduction of P2X7R transcription on neuronal cells at the early and advanced stages, but not at the late stages. Since previous studies have reported that either pharmacological inhibition or selective downregulation of P2X7R significantly improve behavioral alterations and reduce the incidence and size of senile plaques in the early and advanced stages of AD, the results presented here provide new evidences, indicating that this therapeutic approach could also be efficient in the late stages of the disease.