RETROMER TRAFFICKING AND ALZHEIMER'S DISEASE IN DROSOPHILA

果蝇中的逆转录酶贩运和阿尔茨海默氏病

• 批准号: 8574150
• 负责人: Brian D McCabe
• 金额: $ 18.87万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8574150
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein Precursor; Biochemical; Biological Assay; Brain; Cessation of life; Complex; Data; Defect; Drosophila genus; Electrophysiology (science); Endosomes; Enzymes; Genetic Models; Genetic Variation; Hippocampus (Brain); Human; Late Onset Alzheimer Disease; Lead; Link; Locomotion; Longevity; Mammalian Cell; Measures; Mediating; Memory; Modeling; Molecular; Molecular Profiling; Mus; Nerve Degeneration; Neurologic; Neurons; Pathology; Pathway interactions; Patients; Peptides; Proteins; Recycling; Regulation; Research; Risk; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Testing; Transgenic Organisms; Universities; Vacuolar Protein Sorting; base; beta-site APP cleaving enzyme 1; design; fly; glycogen synthase kinase 3 beta; member; neurodegenerative phenotype; neuron loss; novel; overexpression; receptor; receptor binding; response; secretase; sortilin; tau Proteins; tau aggregation; tau phosphorylation; tau-1; trafficking; trans-Golgi Network

Late-Onset Alzheimer's disease (LOAD) is biochemically characterized by abnormal elevations of AB peptide and increased tau phosphorylation. Recently, reduced activity ofthe Retromer complex, which is important for the recycling of transmembrane receptors from endosomes to the Trans-Golgi Network (TGN), has been implicated in the pathology of LOAD from human patient expression profiling. The importance of retromer trafficking to LOAD is supported by several studies including both mouse and Drosophila genetic models of retromer deficiency, which have increased levels of Ap peptide, neurological deficits, and in the fly, extensive neurodegeneration. Defective retromer trafficking also inhibits Wnt signaling, suggesting a pathway via glycogen synthase kinase 3 beta (GSKSp) through which retromer could alter tau phosphorylation. We hypothesize that defective retromer sorting is central to both elevated AB peptide levels and increased tau phosphorylation in LOAD and that modulating retromer trafficking levels will have a positive impact on neurodegeneration. We will test this hypothesis in transgenic Drosophila models of LOAD where human Amyloid Precursor Protein (APP) and Amyloid Precursor Protein li-secretase (BACE) or human Tau are expressed. Our specific aims are designed to determine the molecular pathway that connects retromer deficiency to neurodegeneration and characterize novel interacting proteins that could promote retromer stability.

迟发性阿尔茨海默病（LOAD）的生化特征是AB肽异常升高和tau磷酸化增加。最近，从人类患者表达谱分析中发现，逆转录物复合物活性降低与LOAD病理有关，逆转录物复合物对于从内体到反式高尔基网络（TGN）的跨膜受体的再循环很重要。retromer的重要性