Mechanisms of Amyloid beta-Stimulated ROS in Microglia

小胶质细胞中β淀粉样蛋白刺激ROS的机制

• 批准号: 7172922
• 负责人: BRANDY L WILKINSON
• 金额: $ 5.2万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-11-01 至 2007-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172922
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Brain; Cell Surface Receptors; Cell membrane; Cell surface; Complex; Disease model; Elements; Event; Exposure to; Flavoproteins; Free Radicals; GTP Binding; Generations; Goals; Guanine Nucleotide Exchange Factors; Guanosine Diphosphate; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; In Vitro; Individual; Inflammatory Response; Laboratories; Ligands; Lipids; Mediating; Membrane; Microglia; Monomeric GTP-Binding Proteins; Mus; NADP; Neurons; Oxidases; Pathogenesis; Phenotype; Phosphorylation; Phosphotransferases; Production; Protein Kinase; Protein Overexpression; Protein Tyrosine Kinase; Proteins; Reactive Oxygen Species; Role; Senile Plaques; Signal Pathway; Signal Transduction; Source; Stimulus; System; Tg2576; Thea Plant; Transgenic Mice; Vav guanine-nucleotide exchange factor; base; cytochrome b558; human CYBA protein; membrane assembly; mouse Gdi2 protein; mouse model; neurotoxic; neutrophil cytosol factor 40K; neutrophil cytosol factor 67K; oxidation

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate mechanisms mediating the microglia pro-inflammatory response to fibrillar beta amyloid (fAa). The interaction of microglia with Abeta plaques leads to the induction of proinflammatory signaling cascades and the release of neurotoxic secretory products. Previous studies have shown fAbeta-stimulated ROS production from the activation of microglial NADPH oxidase. The NADPH oxidase consists of the membrane associated flavoprotein cytochrome b558 and the cytosolic, p47phox, p67phox, p40phox, and Rac1. Rac must be GTP-bound to function as part of the oxidase. The cytosolic components, p47phox and p67phox, under go phosphorylation and translocation to the membrane to initiate ROS generation. Little is known about the Abeta-stimulated intracellular signaling pathways responsible for this activation. We hypothesize that fAbeta engagement of a newly discovered multireceptor cell surface complex on microglia leads to the production of ROS and subsequent neuronal damage. This proposal seeks to identify tyrosine kinase-based signaling cascades that activate intracellular signaling elements that function to stimulate assembly and activation of the NADPH oxidase following exposure to fAbeta.

描述（由申请人提供）：