Molecular effects of pharmacological modulation of P2Y6 receptors in an in vitro model for the study of Alzheimer's Disease

Abstract

Alzheimer's Disease (AD) is a neurodegenerative disease often characterized by the accumulation of amyloid beta (A²) plaques and / or neurofibrillary tangles in the brain. AD patients present symptoms that include memory loss, language deficits and motor control impairment, often associated with psychiatric symptoms, such as depression and anxiety. A² plaques and neurofibrillary tangles of Tau protein cause hyperactivation of the neuroimmune response with a consequent increase in the levels of pro inflammatory cytokines. In addition, the sustained activation of microglia and astrocytes can increase the formation of A² plaques, resulting in a continuous and neurotoxic cycle.The purinergic system modulates several processes that are altered in AD, such as glutamate release, immune system activation, and energy balance. This system comprises membrane receptors (P1 and P2) activated by purine nucleotides and nucleosides. Recent studies suggest the involvement of P2Y6 receptors in the pathology of neurodegenerative diseases, especially through the modulation of microglial phagocytic activity and neuroimmune response, which makes it a possible target for the treatment of this disease. For this reason, the present project aims to investigate the effects induced by the pharmacological modulation of P2Y6 receptors in co-culture of neuronal (Sh-sy5y) and microglial (C20) cells incubated with O²A in the formation of A² plaques, neuroplasticity, oxidative stress, inflammatory cytokines levels, cellular viability.