ATP-Binding Cassette Transporter-2 Regulates Amyloid Precursor Protein Dynamics

ATP 结合盒转运蛋白 2 调节淀粉样蛋白前体蛋白动力学

• 批准号: 7934484
• 负责人: WARREN DAVIS
• 金额: $ 16.9万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934484
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Brain; Cells; Cholesterol; Cholesterol Homeostasis; Crossbreeding; Enzymes; Etiology; Generations; Genes; Goals; Homeostasis; Human; In Vitro; Investigation; Knock-out; Knockout Mice; Knowledge; Link; Lysosomes; Mediating; Membrane; Membrane Microdomains; Metabolism; Microarray Analysis; Mus; Mutation; Neuroglia; Neurons; Pathway interactions; Peptides; Prevention; Process; Production; Protein Dynamics; Proteins; Proteolytic Processing; Regulation; Role; Tg2576; Transgenic Mice; Transgenic Organisms; Ursidae Family; amyloid precursor protein processing; base; cholesterol trafficking; clinically relevant; human TAP2 protein; in vivo; late endosome; mind control; mouse model; mutant; novel; promoter; public health relevance; secretase; therapeutic development

DESCRIPTION (provided by applicant): Project Summary: The long-term goals of this project focus on establishing the ATP-binding cassette transporter-2 (ABCA2) as a novel regulator of proteolytic processing of the amyloid precursor protein (APR). Amyloidogenic processing of APP results in the generation of A-beta peptide cleavage products that are implicated in the etiology of Alzheimer's disease (AD). The complete elucidation of the mechanisms that regulate APP processing and Ap production has not been realized. One mechanism that regulates APP processing is the cholesterol trafficking-dependent localization of APP and key enzymes that mediate its proteolytic cleavage in membrane compartments. ABCA2 may function to modulate intracellular cholesterol trafficking of exogenous llpoprotein-derived cholesterol from late-endosomes/lysosomes to membrane compartments. We identified ABCA2 as a regulator of APP processing and A-beta production in vitro. We determined that cellular APP holoprotein levels and A-beta secretion were increased in non-neuronal HEK293 cells that stably co-expressed ABCA2 and APP bearing the APP "Swedish" mutation. We also detected increased expression of a number of genes associated with AD using microarray analysis in HEK293 cells that stably expressed ABCA2. Although evidence suggests that ABCA2 may be a key regulator of APP metabolism, perhaps by regulation of intracellular cholesterol trafficking and distribution, we have not examined the effects of ABCA2 function in either neuronal cells or in the brains of transgenic mice expressing mutant forms of APP. Our recent production of ABCA2 knockout mice and ABCA2 transgenic mice under the control of the brain-specific Thy-1 promoter will permit the investigation of this novel function of the ABCA2 transporter in regulating APP processing and A-beta production in vivo in transgenic mouse models of AD. Our preliminary results have led us to the novel hypothesis that ABCA2 acts to regulate APP processing and A-beta production through modulation of intracellular cholesterol trafficking-dependent localization of APP and key processing enzymes in membrane compartments. Public Health Relevance: These studies may provide novel and mechanistic links between cholesterol metabolism and APP processing that could be of direct clinical relevance. In depth knowledge of the mechanisms of action of the ABCA2 transporter on regulation of APP processing may provide a basis for the development of therapeutic strategies in prevention and treatment of AD.

描述（由申请人提供）：项目摘要：该项目的长期目标着重于建立ATP结合纸盒转运蛋白-2（ABCA2）作为淀粉样蛋白蛋白质蛋白水解加工的新调节剂（APR）。 APP的淀粉样生成加工会导致与阿尔茨海默氏病（AD）病因相关的A-beta肽裂解产物的产生。尚未实现调节应用程序处理和AP生产的机制的完全阐明。调节APP处理的一种机制是APP和关键酶的胆固醇运输依赖性定位，可介导其在膜室中的蛋白水解裂解。 ABCA2可能会在调节外源性llpoprotoin衍生的胆固醇的细胞内胆固醇运输从晚期/溶酶体到膜室。我们将ABCA2确定为体外应用程序加工和A-beta生产的调节剂。我们确定在非神经元HEK293细胞中增加了细胞APP的全蛋白水平和A-beta分泌，这些细胞稳定地共表达ABCA2和带有应用程序“瑞典”突变的APP。我们还检测到使用稳定表达ABCA2的HEK293细胞中的微阵列分析，与AD相关的许多基因的表达增加。尽管有证据表明ABCA2可能是APP代谢的关键调节剂，但也许是通过调节细胞内胆固醇运输和分布的调节，但我们尚未检查ABCA2功能在神经元细胞中的作用或表达App的突变体形式的转基因小鼠的大脑。我们最近在大脑特异性THY-1启动子控制下对ABCA2基因敲除小鼠和ABCA2转基因小鼠的控制，将允许研究ABCA2转运蛋白在调节AD的AD型APP处理和A-BETA生产中的这种新功能。我们的初步结果使我们提出了这样一种新的假设，即ABCA2通过调节APP的细胞内胆固醇运输依赖性定位和膜室中的关键加工酶来调节APP处理和A-BETA生产。 公共卫生相关性：这些研究可能会提供胆固醇代谢和应用程序处理之间的新颖和机械联系，这可能是直接临床相关性的。在深入了解ABCA2转运蛋白对应用程序处理调节的作用机理的知识中，可以为预防和治疗AD的治疗策略发展提供基础。