Behavioral and molecular effects of pharmacological modulation of the P2Y2 receptors in an animal model of Alzheimer's Disease

Abstract

Alzheimer's Disease (AD) is a disabling psychiatric disorder that affects approximately 18 million people worldwide. The causes of this disorder are not well elucidated given their complexity, and the symptoms generally progress from memory loss to language and motor impairment, often including depression. Despite its great impact on the patient, family and society, the therapies available for this disorder are ineffective and only palliative. Therefore, the study of the mechanisms involved in the pathogenesis of AD has an essential role in the search for new pharmacological targets for its treatment. P2Y2 receptors (P2Y2R) are activated by adenosine triphosphate (ATP) and uridine triphosphate (UTP) and are coupled to Gq protein. The stimulation of these receptors promotes the activation of the pathway phospholipase C (PLC) / inositol 1,4,5-triphosphate (IP3) / protein kinase C (PKC), besides regulating the migration, proliferation and release of growth factors. Studies still suggest a neuroprotective role of P2Y2R receptors in AD. However, the evaluation of these receptors function on the molecular and behavioral changes related to the cognitive and depressive symptoms of AD in mice treated intra-cerebroventricular (i.c.v.) with amyloid-² oligomers (AßO), an in vivo model of sporadic AD, was never investigated. Based on this, the present project intends to analyze the effect of the P2Y2R modulation (agonist or antagonist i.c.v. infusion) on the recognition memory (object recognition test), depressive-related behaviors (forced swimming test and sucrose preference) and molecular changes (Tau protein, enzymes that regulate the levels of A²1-42, proteins involved of neuroplastic, neurotoxic and neuroinflammatory processes) related to AD in the prefrontal cortex (CPF) and hippocampus (Hpc) of mice i,c.v, treated with A²O. In addition, the effect of i.c.v. infusion with P2Y2R agonist or antagonist on expression of neuronal and glial markers in the CPF and Hpc of these animals will also be evaluated. (AU)