Octyl gallate (OG) and Promotion of non-amyloidogenic processing of APP

没食子酸辛酯 (OG) 和促进 APP 的非淀粉样蛋白加工

• 批准号: 8803251
• 负责人: Jun Tan
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803251
• 关键词: Accounting; Age; Agonist; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Amyloidosis; Behavior; Brain; Cells; Cerebrum; Chronic; Cleaved cell; Cultured Cells; Dementia; Development; Direct Costs; Disease; Drug Targeting; Elderly; Epigallocatechin Gallate; Estrogen Receptors; Evaluation; Event; Facilities and Administrative Costs; Frequencies; Future; Gallic acid; Generations; Goals; Health; Health Care Costs; Healthcare; Human; Impaired cognition; Impairment; In Vitro; Individual; Investigation; Length; Life; Longitudinal Studies; Mediating; Mediation; Memory; Molecular; Mus; Neurons; PI3K/AKT; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Physical Function; Plants; Play; Prevalence; Production; Proteins; Proteolysis; Proteolytic Processing; Receptor Signaling; Recombinants; Regulation; Research; Role; Signal Pathway; Signal Transduction; Tannic Acid; Tertiary Protein Structure; Tg2576; Transgenic Mice; Veterans; Work; aged; alpha secretase; amyloid pathology; amyloid precursor protein processing; base; beta-site APP cleaving enzyme 1; effective therapy; in vivo; insight; mouse model; novel; peptide A; prevent; research study; secretase

DESCRIPTION (provided by applicant): Therapies opposing cleavage of amyloid precursor protein (APP) into A¿ peptides and resultant cerebral amyloidosis, a key pathological feature of AD, have become a primary focus in recent years. The main targets have been ¿- and ?-secretase, the two proteases that cleave APP at the amino and carboxyl-terminus of the A¿ peptide, respectively and, hence, are responsible for A¿ peptide generation. An alternative strategy, the activation of ¿-secretase, has scarcely been investigated. ¿-secretase cleaves APP within the A¿ peptide domain and precludes its generation, thereby promoting the non-amyloidogenic pathway of APP proteolysis. ¿-secretase activation also generates the putatively neuroprotective sAPP-¿. In addition, previous studies have shown that enhanced activation of ADAM10, a primary candidate ¿-secretase, has reduced A¿ generation and prevented cognitive impairment in a mouse model of AD. Our previous findings suggest that EGCG promotes non-amyloidogenic APP proteolysis by in vitro activation of ADAM10 and, similarly, prevent ¿-amyloid pathology in vivo. Recently, we found that EGCG functions through an estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP. Further these events are positively correlated with presence of the gallate group of these phenolic compounds. Furthermore, we have shown that octyl gallate (OG) has a significantly profound effect on promoting ¿-secretase cleavage of APP thus limiting A¿ production in neuron-like N2a cells expressing human wild-type APP compared to EGCG. Most recently, we found that exogenous human recombinant sAPP-¿ protein promotes non-amyloidogenic APP proteolytic processing through specifically interacting with BACE1, a primary ¿-secretase candidate, in cultured cells. This interaction of sAPP-¿ with BACE1 inhibited its subsequent cleavage of full-length APP and resultant further decreased A¿ generation. The goal of the proposed research is to define this non-amyloidogenic mechanism in OG and identify potential molecular drug targets, which are essential for formulating novel, effective treatments against AD. In this proposal we hypothesize that ADAM10 activating compound, octyl gallate (OG) produced from the gallic acid of various plant tannins, will increase non-amyloidogenic/alpha-secretase proteolysis of APP, and reduce cerebral amyloidosis in a transgenic mouse model of AD. We expect to clearly define this non-amyloidogenic APP processing mechanism promoted by OG, and, consequently, identify potential molecular drug targets, which are essential for formulating novel, effective treatments against AD. This work will be completed by investigation of the following aims: (I) Investigate the role of estrogen receptor (ER) signaling in OG-promoted anti-amyloidogenic APP ¿-secretase proteolysis; Characterize sAPP-¿ mediation of OG-induced anti-amyloidogenic APP processing; (III) In vivo evaluation of the effect of octyl gallate (OG) for the promotion of anti-amyloidogenic APP ¿-secretase proteolysis. At the end of these experiments, these studies will provide the molecular basis for the future development of OG as novel and pharmacologically safe agents for Alzheimer's disease prevention/treatment.

描述（由申请人提供）： 与淀粉样蛋白前体蛋白（APP）裂解相对的疗法，AD的关键病理特征已成为近年来的主要重点。主要靶标是 - 分泌酶，分别在A肽的氨基和羧基末端清除应用程序的两个蛋白酶，因此是肽产生的原因。几乎没有研究过一种替代策略，即`` - 分泌酶的激活''。 - 分泌酶在A肽结构域内切割应用并排除其产生，从而促进了APP蛋白水解的非淀粉样蛋白生成途径。 - 分泌酶活性还会产生推定的神经保护性SAPP-®。此外，先前的研究表明，ADAM10的激活增强是一种主要的候选„ - 分泌酶，从而降低了A的生成并阻止了AD小鼠模型中的认知障碍。我们以前的发现表明，EGCG通过体外ADAM10的体外激活促进非淀粉样蛋白生成的APP蛋白水解，并类似地预防体内»淀粉样病理学。最近，我们发现EGCG通过雌激素受体介导的ADAM10激活在促进APP的非淀粉样生成过程中起作用。此外，这些事件与这些酚类化合物的食道酸酯组的存在正相关。此外，我们已经表明，八列酸酯（OG）对促进APP的 - 分泌酶的裂解具有显着深远的作用，从而限制了与EGCG相比，表达人类野生型APP的神经元样的N2A细胞的产生。最近，我们发现外源的人重组SAPP-蛋白质通过与培养细胞中的原代分泌酶候选者BACE1特异性相互作用，促进非淀粉样蛋白生成的APP蛋白水解加工。 Sapp-€与Bace1的这种相互作用抑制了其随后的全长应用程序的分裂，因此结果进一步下降了A的一代。拟议的研究的目的是定义OG中的这种非淀粉样蛋白生成机制并确定潜在的分子药物靶标，这对于制定针对AD的新型有效治疗至关重要。 在此提案中，我们假设ADAM10激活化合物，八宁酸的五藻酸八叶酸酯（OG），将增加非淀粉样蛋白/α-分泌酶蛋白水解的APP的非淀粉样蛋白/α-分泌酶的蛋白水解，并减少脑淀粉样蛋白的AD，在AD的AD的脑淀粉样蛋白中。我们期望明确定义由OG促进的这种非淀粉样蛋白生成的应用程序处理机制，因此，确定了潜在的分子药物靶标，这对于制定针对AD的新型有效治疗至关重要。这项工作将通过研究以下目的来完成：（i）研究雌激素受体（ER）信号在OG促进的抗淀粉样蛋白生成应用中的作用。-分泌酶蛋白水解；表征了OG诱导的抗淀粉样生成应用程序的SAPP-介质； （iii）在体内评估八列酸酯（OG）对 促进抗淀粉样生成应用程序 - 分泌酶蛋白水解。在这些实验结束时，这些研究将为OG的未来发展提供分子基础，作为新颖的和药物在阿尔茨海默氏病预防/治疗中的新型和药物安全。