GGPP-mediated modulation of APP processing

描述(申请人提供)：他汀类药物在体外和体内都可以减少A？的生成，这为其在阿尔茨海默病(AD)预防中的临床益处提供了可能的解释。然而，研究表明，在使用阿托伐他汀治疗的转基因AD小鼠模型中，或在转基因小鼠中血液胆固醇水平较低的小鼠中，胆固醇和A？的水平并不相关。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，他汀类药物可抑制甲氧戊酸下游代谢产物的生物合成，包括胆固醇和类异戊二烯。我们发现香叶基香叶基焦磷酸(GGPP)是甲戊酸生物合成途径中产生的一种异戊二烯类化合物，它通过激活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片段的切割依赖于GGPP。此外，补充GGPP可完全逆转他汀类药物介导的A？降低作用。根据我们的发现，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；并且通过抑制GGPP的合成，他汀类药物减少A？的生成。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的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类药物介导的APP-CTF处理和特定目标#2的A？生成变化的机制。拟议的研究产生的信息将拓宽我们对他汀类药物治疗AD机制的认识，并提供更特异的药物靶点。我们的研究也将为未来的研究开发基于异戊二烯和Rho/Rock信号调节的预防AD的新治疗方法奠定基础。他汀类药物已被证明可以降低阿尔茨海默病的患病率，它抑制胆固醇和GGPP的合成。我们发现GGPP改变了APP的代谢，促进了淀粉样多肽的合成，这是一种在疾病发展中至关重要的蛋白质。我们将能够通过拟议的研究来确定潜在的机制，从而为阿尔茨海默病的预防和治疗提供新的药物靶点。

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.