Neuroprotective roles of the P2Y[subscript 2] nucleotide receptor

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Alzheimer's disease (AD) is the most prevalent neurodegenerative disease. AD is an important disease to study because of the high cost of care for individuals with AD and the burden on their families and/or caretakers. This research utilized mouse models of AD and cell cultures to study the neuroprotective roles of P2Y2 receptor, a protein expressed in a number of human and animal tissues. This receptor is expressed at higher levels in the brains of a mouse model of Alzheimer's disease (AD) than in wild type mice. One cause of this increase in P2Y2 receptor expression is inflammation. This research indicates that the activation of the P2Y2 receptor under inflammatory conditions increases neuronal cell growth and regulates other neuroprotective responses. Additional work shows that when the P2Y2 receptor gene is deleted in a mouse model of AD, accelerated AD-like symptoms and premature death occur. The loss of the P2Y2 receptor may also contribute to accelerated memory impairment in these mice. Overall, this research shows that the P2Y2 receptor plays a role in protecting the brains of mice from the consequences of AD and therefore, the P2Y2 receptor may also represent a novel target for treatment of AD in humans. Purinergic signaling plays a unique role in the brain by integrating neuronal and glial cellular circuits. The metabotropic P1 adenosine receptors and P2Y nucleotide receptors and ionotropic P2X receptors control numerous physiological functions of neuronal and glial cells and have been implicated in a wide variety of neuropathologies. Emerging research suggests that purinergic receptor interactions between cells of the central nervous system (CNS) have relevance in the prevention and attenuation of neurodegenerative diseases resulting from chronic inflammation. CNS responses to chronic inflammation are largely dependent on interactions between different cell types (i.e., neurons and glia) and P2X and P2Y receptors. Whereas numerous P2 receptors contribute to functions of the CNS, the P2Y2R is believed to play an important role in neuroprotection under inflammatory conditions. While acute inflammation is necessary for tissue repair due to injury, chronic inflammation contributes to neurodegeneration in Alzheimer's disease (AD) and occurs when glial cells undergo prolonged activation resulting in extended release of proinflammatory cytokines and nucleotides. This review describes cell-specific and tissue-integrated functions of P2 receptors in the CNS with an emphasis on P2Y2R signaling pathways in neurons, glia and endothelium and their role in neuroprotection