The role of chemoattractant receptors in central nervous system diseases

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DESCRIPTION (provided by applicant): Inflammation plays an important role in central nervous system (CNS) infection and the progression of neurodegenerative diseases such as HIV-associated dementia and Alzheimer's disease (AD). The presence of an abundant number of activated microglial cells in amyloid plaques and the elevated levels of pro-inflammatory molecules in CNS support the contribution of chemoattractant receptors and inflammation to the pathogenesis of AD. It is clear that a balance between pro- and anti-inflammatory signals in the CNS is important in the initiation and progression of AD. Interleukin 4 (IL-4) and other anti-inflammatory cytokines, such as IL-13, differentially regulate microglial responses to amyloid beta 1-42 (A242), the pathogenic peptide in AD; which indicates that IL-4 and IL-13 have the potential to regulate inflammatory processes associated with this neurodegenerative disease. All these evidences prompted us to hypothesize that IL-4, by regulating the activation of microglial cells and its expression of key chemoattractant receptors that participate in neuroinflammation, may provide protection against the deleterious effects of proinflammatory stimuli in the CNS. The specific aims of this study are: 1) To evaluate the effects of IL-4 on the survival and activation of microglial cells. 2) To examine the regulation of chemoattractant receptors in macrophages and microglia by interleukin 4. 3) To further dissect the signaling pathways involved in the effects of IL-4 on microglial cells. Significance: The completion of these goals will provide insights into the role of IL-4 in the regulation of neuroinflammation and the definition of potential molecular targets for the development of therapeutic approaches to treat AD and neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: The presence of an abundant number of activated microglial cells in the brain support the contribution of chemoattractant receptors and inflammation to the pathogenesis of Alzheimer's disease (AD). Interleukin 4 (IL- 4) may provide protection against the deleterious effects of pro-inflammatory stimuli in the central nervous system. The completion of the goals proposed in this project will provide insights into the role of IL-4 in the regulation of neuroinflammation and the definition of potential molecular targets for the development of therapeutic approaches to treat AD and other neurodegenerative diseases.