Study on the role of purinergic-endocannabinoid interplay in Alzheimer's Disease and comorbid depression

Abstract

Alzheimer's Disease (AD) and major depression (MD) are highly comorbid conditions which have no effective treatment recently available to prevent their chronification. This situation may be ascribed to the translational gap between animal-based models used in preclinical studies and patients as well as under-explored pathological mechanisms underlying AD and MD. Aiming to address these issues, I will first establish an in vitro model to study core mechanisms involved in AD and MD neuropathologies by using human induced pluripotent stem cell (hiPSC) lines generated from apolipoprotein E4 (APOEµ4) homozygote carriers (the main genetic risk factor for AD) treated with cortisol (a widely known consequence of stress exposure, the main environmental risk factor for AD and MD). Second, I will investigate the possibility to correct the shared dysregulated pathways in AD and MD by targeting the interplay between specific purinergic receptors (P2X7R and P2Y2R) and endocannabinoid (eCB) signaling in this model. P2X7R and P2Y2R activation may induce neurotoxic (increased inflammation) and neuroprotective (increased neuroplasticity) effects associated with mental disorders, respectively. These receptors are also key players in the regulation of 2-arachidonoylglycerol (2-AG), the main eCB and involved in stress adaptation. P2Y2R stimulates the synthesis and degradation of 2-AG under resting conditions, whereas P2X7R promotes 2-AG accumulation under neurotoxic conditions. Considering that increased 2-AG levels are mainly associated with CB2-mediated anti-inflammatory effects and increased neuroplasticity, I propose that the increase in 2-AG levels observed in neurotoxic conditions may be a failed attempt to counterbalance P2X7R-mediated neuroinflammation. Thus, I will investigate if the P2X7R blockade or P2Y2R activation, alone or in combination with the inhibition of 2-AG degradation, can revert molecular alterations involved in AD and MD neuropathology in the proposed model. (AU)