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One current hypothesis regarding the pathogenesis of Alzheimer’s disease (AD) is the amyloid cascade/neuroinflammation hypothesis. This theory states that insoluble deposits of the beta amyloid protein (Aß) in the brain chronically activate local glial cells, called microglia, which then produce neurotoxins that cause damage to neurons. If this neuro-inflammatory response to Aß persists, it causes loss of synaptic connections, resulting in the cognitive dysfunction and dementia observed in AD patients. Therefore, drugs that attenuate microglial activation and interrupt the neurodegenerative process may delay or halt the progression of the disease. A prerequisite for the discovery of these anti-inflammatory drugs is the identification and validation new therapeutic targets. A large number of preclinical studies have shown that microglial activation is determined by the interaction of molecules found on the surface of neurons and microglia. To date, little is known about the identity and biochemical nature of these molecules involved in this interplay, but recent studies focus attention on one particular molecule, fractalkine, which is found to be present on the surface of most neurons of the CNS. The receptor that binds fractalkine is present on microglial cells, suggesting that the fractalkine-fractalkine receptor system may represent a mechanism through which neurons control the state of microglial activation. In general, drug discovery has been hampered, in part, by the lack of validated therapeutic targets that provide the starting points for medicinal chemists for the synthesis of novel drugs for the treatment of AD. The overall goal of this program is to validate new anti-inflammatory drug targets. The results from these studies will guide future development of therapeutic agents designed to modulate microglial activation and therefore, stop or slow the progression of AD.