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（由申请人提供）：他汀类药物可以在体外和体内减少A¿的产生，这可能解释了其在阿尔茨海默病（AD）预防方面的临床益处。然而，研究表明，在接受阿托伐他汀治疗的转基因AD小鼠模型或通过基因工程使血液胆固醇水平降低的小鼠中，胆固醇水平和A¿水平并不相关。因此，他汀类药物仅仅通过降低胆固醇起作用的观点可能需要更仔细地检验。作为HMG-CoA还原酶的抑制剂，他汀类药物抑制甲羟戊酸下游许多代谢物的生物合成，包括胆固醇和类异戊二烯。我们发现，在甲羟戊酸生物合成途径中产生的类异戊二烯类香叶香叶基焦磷酸（GGPP）通过激活Rho/Rock信号优先增加淀粉样蛋白A¿42的水平。我们还发现分泌酶对APP片段的裂解是依赖于GGPP的。此外，补充GGPP可以完全逆转他汀类药物介导的A¿降低。基于我们的研究结果，我们假设细胞GGPP可能在AD的淀粉样蛋白形成中发挥重要作用；通过抑制GGPP的合成，他汀类药物减少A¿的产生。为了验证这一假设，我们将首先确定细胞GGPP水平与特定目标#1中A¿生成之间的关系。然后，我们将研究Rho/Rock信号的抑制是否是他汀介导的APP-CTF加工和a¿生成变化的机制。拟议研究产生的信息将扩大我们对他汀类药物治疗AD机制的认识，并提供更具体的药物靶点。我们的研究也将为未来的研究奠定基础，开发基于类异戊二烯和Rho/Rock信号调节的新型治疗方法来预防AD。他汀类药物抑制胆固醇和GGPP的合成，已被证明可以降低阿尔茨海默病的患病率。我们发现GGPP改变了APP的代谢，促进了淀粉样蛋白肽的合成，淀粉样蛋白肽是一种在疾病发展中很重要的蛋白质。我们将能够通过拟议的研究确定潜在的机制，从而为预防和治疗阿尔茨海默病提供新的药物靶点。