Alzheimer's disease (AD) is the leading cause of dementia in the elderly. It is characterized by distinct neuropathological hallmarks including extracellular deposits of beta-amyloid (A-beta) and marked microglial activation. At present, there is no effective therapy, and the burden of AD will continue to grow as the population ages. There is substantial evidence that neuroinflammation contributes directly to AD pathophysiology. In particular, long-term non-steroidal anti-inflammatory drug regimen has been consistently associated with reduced AD risk. However, the role of microglia, the primary immune effector cells in the brain, remains unclear. Whereas microglia are found in the AD brain in a chronically activated state with up-regulation of neurotoxic cytokines, they may also restrict the growth of A-beta deposits by phagocytosing Ap. Recent experimental evidence has shown that fractalkine chemokine signaling pathways mediated by the microglial receptor CX3CR1 play an important role in regulating microglial activation. Preliminary studies demonstrated that in APPPS1 mouse model of AD, Cx3cr1 deficiency confers a gene dose dependent reduction in A-beta deposition and microglial activation. The current proposal seeks to extend these findings and examine the role of neuroinflammation in AD pathogenesis by characterizing the microglial phenotype and function in Cx3cr1 deficient APPPS1 mice. The long-term goal of this project is to discover new therapeutic approaches for AD by investigating how alterations in microglial activation ameliorate AD neuropathology. The specific aims of the project are described below; In Specific Aim 1, purified microglia from APPPS1 mice with Cx3cr1 deficiency will be examined for pro- and anti-inflammatory surface markers and transcripts. In Specific Aim 2, brain sections from APPPS1 mice with Cx3cr1 deficiency will be examined for evidence of alterations in microglial proliferation and apoptosis. In Specific Aim 3, Cx3cr1-deficient microglia will be examined for their capacity to phagocytose A-beta and migrate to stereotactically injected A-beta.