GGPP-mediated modulation of APP processing

GGPP 介导的 APP 加工调节

• 批准号: 7303581
• 负责人: YAN ZHOU
• 金额: $ 6.82万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7303581
• 关键词: Aftercare; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Anabolism; Blood; Brain; C-terminal; Cardiovascular Diseases; Cholesterol; Clinical; Complex; Detergents; Development; Disease; Drug Delivery Systems; Epidemiologic Studies; Future; Generations; Genetically Engineered Mouse; Geranylgeranyl-diphosphate geranylgeranyltransferase; Health; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro; Knowledge; Mediating; Membrane; Membrane Microdomains; Metabolism; Monomeric GTP-Binding Proteins; Pathway interactions; Patients; Peptides; Play; Population; Post-Translational Protein Processing; Prevalence; Prevention; Process; Protein C; Protein Fragment; Proteins; Regulation; Reporting; Research; Role; Signal Transduction; Small Interfering RNA; Testing; Transgenic Organisms; amyloid peptide; amyloid precursor protein processing; amyloidogenesis; atorvastatin; base; clinically relevant; disorder prevention; farmer; geranylgeranyl pyrophosphate; in vivo; insight; isoprenoid; mevalonate; mouse model; novel; novel therapeutics; prevent; rho; secretase

DESCRIPTION (provided by applicant): Statins can reduce A¿ generation both in vitro and in vivo, which provides a possible explanation for their clinical benefits in Alzheimer's disease (AD) prevention. However, it has been shown that the levels of cholesterol and A¿ are not correlated in the brain of transgenic AD mouse models treated with atorvastatin or in mice genetically engineered to have low blood cholesterol levels. Therefore, the notion that statins act simply via cholesterol-lowering may need to be examined more carefully. As inhibitors of HMG-CoA reductase, statins inhibit the biosynthesis of many metabolites downstream of mevalonate, including cholesterol and isoprenoids. We have found that geranylgeranyl pyrophosphate (GGPP), an isoprenoid generated in the mevalonate biosynthetic pathway, preferentially increases the levels of amyloidogenic A¿42 through the activation of Rho/Rock signaling. We have also found that the cleavage of APP fragments by secretase is GGPP dependent. Furthermore, supplement of GGPP can fully reverse statin-mediated A¿ reduction. Based on our findings, we hypothesize that cellular GGPP may play an important role in the amyloidogenesis of AD; and through inhibiting the synthesis of GGPP, statins reduce A¿ generation. To test this hypothesis, we will first determine the relation between cellular GGPP levels and and A¿ generation in specific aim #1. We will then investigate whether the inhibition of Rho/Rock signaling is a mechanism of statin-mediated changes in APP-CTF processing and A¿ generation in specific aim #2. The information generated by the proposed studies will broaden our knowledge of the mechanisms of statins in the treatment of AD and provide more specific drug targets. Our studies will also set a start point for future research to develop novel therapeutic approaches to prevent AD based on the regulation of isoprenoids and Rho/Rock signaling. Statins, which have been shown to reduce the prevalence of Alzheimer's disease, inhibit the synthesis of both cholesterol and GGPP. We have found that GGPP alters the metabolism of APP and promote the synthesis amyloid-¿-peptide, a protein important in the development of the disease. We will be able to define the underlying mechanisms through proposed studies, thus providing new drug targets for the prevention and treatment of Alzheimer's disease.

描述（由应用程序提供）：他汀类药物可以在体外和体内减少生成，这为他们在阿尔茨海默氏病（AD）预防中的临床益处提供了一种可能的解释。然而，已经表明，在用阿托伐他汀治疗的转基因AD小鼠模型的大脑中，胆固醇和A的水平不相关，或者在基因工程上具有低血液胆固醇水平的小鼠。因此，只需通过降低胆固醇来起作用他汀类药物的观念可能需要更加仔细地检查。随着HMG-COA的抑制剂减少，他汀类药物抑制了甲瓦龙酸酯下游的许多代谢物的生物合成，包括胆固醇和异胞菌素。我们已经发现，在甲酸盐生物合成途径中产生的类异磷酸乙酸焦磷酸（GGPP）最好通过激活Rho/Rock信号来提高淀粉样蛋白生成型42的水平。我们还发现，分泌酶对App片段的裂解取决于GGPP。此外，GGPP的补充可以完全逆转他汀类药物介导的减少。根据我们的发现，我们假设细胞GGPP可能在AD的淀粉样生成中起重要作用。通过抑制GGPP的合成，他汀类药物减少了生成。为了检验这一假设，我们将首先确定特定目标1中细胞GGPP水平和A生成之间的关系。然后，我们将研究Rho/Rock信号传导的抑制是汀类药物介导的APP-CTF处理变化和特定目标＃2中的A e生成的机制。拟议的研究产生的信息将扩大我们对AD治疗统计机制的了解，并提供更具体的药物靶标。我们的研究还将为未来的研究设定一个起点，以开发新型的治疗方法，以防止基于类异丙因和RHO/ROCK信号的调节。他汀类药物已被证明降低了阿尔茨海默氏病的患病率，抑制了胆固醇和GGPP的合成。我们发现GGPP改变了APP的代谢，并促进合成淀粉样蛋白肽，这是一种对疾病发展重要的蛋白质。我们将能够通过拟议的研究来定义潜在的机制，从而为预防和治疗阿尔茨海默氏病提供新的药物靶标。