ATP-BINDING CASSETTEE TRANSPORTER-2 (ABCA2) REGULATION OF BETA APP PROCESSING

ATP 结合盒转运蛋白 2 (ABCA2) Beta APP 处理的调节

• 批准号: 7381855
• 负责人: WARREN DAVIS
• 金额: $ 17.82万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381855
• 关键词: ATP; BINDING; CASSETTEE; TRANSPORTER; ABCA2

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Amyloidogenic processing of APP results in the generation of Abeta peptide fragments that are involved in the etiology of Alzheimer¿s disease (AD). The complete elucidation of the mechanisms that regulate APP processing has not been realized. We undertook a screen of ATP-binding cassette transporters expressed in the brain for their effects on APP metabolism. Our current results suggest that the ATP-binding cassette transporter (ABCA2) is a regulator of APP processing and Abeta production. Genetic evidence by single nucleotide polymorphism (SNP) mapping identified a single synonymous mutation in ABCA2 that is significantly associated with early-onset AD. We determined that ABCA2 overexpression in HEK293 cells bearing the APP Swedish mutation (APPsw) increased cellular APP holoprotein levels and Abeta secretion. Using microarray analysis of gene expression profiles in HEK293 cells stably transfected with ABCA2, we detected elevated levels of a number of genes associated with AD. Although these findings suggest that ABCA2 may be a key regulator of APP metabolism, ABCA2 regulation of APP processing was not examined in either neuronal cells or in transgenic mice expressing mutant forms of APP. The recent production of an ABCA2 knockout mouse will permit the unequivocal determination of the function of the ABCA2 transporter in regulating APP processing and Abeta production in vivo. We do not know the physiological significance of ABCA2 in regulating APP processing and Abeta production. A central hypothesis of this COBRE project is that ABCA2 functions in neuronal cells to regulate APP processing and Abeta production and thereby serves a critical role in maintaining homeostasis between amyloidogenic and non-amyloidogenic pathways of APP metabolism. We shall undertake experiments to determine if ABCA2 protein levels modulate APP processing and the consequences for neuropathology and learning performance in transgenic mouse models of the disease.

该子项目是由NIH/NCRR资助的许多子项目之一。一定是研究者。 S疾病（AD）。 ABETA生产。在APP代谢中，在神经元细胞或重新产生ABCA2敲除小鼠的突变体形式的转基因小鼠中，ABCA2的调节均不得我们的生产。学习性能N疾病的转基因小鼠模型。