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
基本信息
- 批准号:8441038
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AccountingAgeAgonistAlzheimer disease preventionAlzheimer&aposs DiseaseAmyloid beta-Protein PrecursorAmyloidosisBehaviorBrainCellsCerebrumChronicCleaved cellCultured CellsDementiaDevelopmentDirect CostsDiseaseDrug TargetingElderlyEpigallocatechin GallateEstrogen ReceptorsEvaluationEventFacilities and Administrative CostsFrequenciesFutureGallic acidGenerationsGoalsHealth Care CostsHealthcareHumanImpaired cognitionImpairmentIn VitroIndividualInvestigationLengthLifeLongitudinal StudiesMediatingMediationMemoryMolecularMusNeuronsPI3K/AKTPathway interactionsPatientsPeptide HydrolasesPeptidesPhysical FunctionPlantsPlayPrevalenceProductionProteinsProteolysisProteolytic ProcessingReceptor SignalingRecombinantsRegulationResearchRoleSignal PathwaySignal TransductionTannic AcidTertiary Protein StructureTg2576Transgenic MiceVeteransWorkagedalpha secretaseamyloid pathologyamyloid precursor protein processingbasebeta-site APP cleaving enzyme 1effective therapyin vivoinsightmouse modelnovelpreventpublic health relevanceresearch studysecretase
项目摘要
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):
对抗淀粉样前体蛋白 (APP) 裂解为 A¿ 的疗法肽和由此产生的脑淀粉样变性(AD 的一个关键病理特征)已成为近年来的主要焦点。 - 和 ?-分泌酶,这两种蛋白酶可在 A¿ 的氨基和羧基末端切割 APP肽,分别 和,因此,负责 A¿肽生成的另一种策略是激活 ¿ -分泌酶,几乎没有被研究过。 -分泌酶在A¿内切割APP肽结构域并阻止其生成,从而促进 APP 蛋白水解的非淀粉样蛋白生成途径。 -分泌酶激活还产生假定的神经保护性 sAPP-¿此外,之前的研究表明,ADAM10(主要候选者)的激活增强 ¿ -分泌酶,减少了A¿我们之前的研究结果表明,EGCG 通过体外激活 ADAM10 促进非淀粉样蛋白 APP 蛋白水解,并且同样可以预防 ¿最近,我们发现 EGCG 通过雌激素受体介导的 ADAM10 激活来促进 APP 的非淀粉样蛋白加工,此外,这些事件与这些酚类化合物的没食子酸酯基团的存在呈正相关。此外,我们已经证明没食子酸辛酯 (OG) 对促进 ¿ - APP 的分泌酶裂解从而限制 A¿与 EGCG 相比,表达人野生型 APP 的神经元样 N2a 细胞的产量最近,我们发现外源人重组 sAPP-¿蛋白质通过与 BACE1(主要的 ¿)特异性相互作用,促进非淀粉样蛋白 APP 蛋白水解加工。 -sAPP-¿ 的这种相互作用是培养细胞中的候选分泌酶。 BACE1 抑制其随后对全长 APP 的切割,从而进一步降低 A¿本研究的目标是确定 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点,这对于制定针对 AD 的新型有效治疗方法至关重要。
在本提案中,我们研究了 ADAM10 激活化合物,由各种植物单宁的没食子酸产生的没食子酸辛酯 (OG),将增加 APP 的非淀粉样蛋白/α-分泌酶蛋白水解,并减少 AD 转基因小鼠模型中的脑淀粉样变性。我们期望明确定义 OG 促进的这种非淀粉样蛋白生成 APP 加工机制,从而确定潜在的分子药物靶点,这对于制定针对该疾病的新颖、有效的治疗方法至关重要。 AD。这项工作将通过研究以下目标来完成:(I)研究雌激素受体(ER)信号在 OG 促进的抗淀粉样蛋白生成 APP 中的作用 ¿ -分泌酶蛋白水解;表征 sAPP-¿ (三)没食子酸辛酯(OG)作用的体内评价
促进抗淀粉样蛋白生成 APP¿ -分泌酶蛋白水解。在这些实验结束时,这些研究将为 OG 作为预防/治疗阿尔茨海默病的新型且药理学安全的药物的未来发展提供分子基础。
项目成果
期刊论文数量(0)
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Jun Tan其他文献
Jun Tan的其他文献
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{{ truncateString('Jun Tan', 18)}}的其他基金
Identification of novel APP-specific alpha secretase in human umbilical cord blood sera
人脐带血血清中新型 APP 特异性 α 分泌酶的鉴定
- 批准号:
9380529 - 财政年份:2017
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A flavonoid gamma-secretase modulator (GSM) reduces beta-amyloid and tau pathologies in the AD mice
类黄酮 γ 分泌酶调节剂 (GSM) 可减少 AD 小鼠的 β-淀粉样蛋白和 tau 蛋白病理
- 批准号:
9127058 - 财政年份:2015
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-- - 项目类别:
A flavonoid gamma-secretase modulator (GSM) reduces beta-amyloid and tau pathologies in the AD mice
类黄酮 γ 分泌酶调节剂 (GSM) 可减少 AD 小鼠的 β-淀粉样蛋白和 tau 蛋白病理
- 批准号:
8976888 - 财政年份:2015
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Flavonoid-diosmin modulation of Abeta and tau pathologies through GSK-3 signaling
类黄酮-地奥司明通过 GSK-3 信号传导调节 Abeta 和 tau 病理学
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8627446 - 财政年份:2014
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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 - 财政年份:2013
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IL-6-mediated Jak2/Stat3 signaling and Brain Development
IL-6 介导的 Jak2/Stat3 信号传导与大脑发育
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8135535 - 财政年份:2010
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IL-6-mediated Jak2/Stat3 signaling and Brain Development
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7985709 - 财政年份:2010
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Implication of HUCBC: a novel therapeutic strategy for Alzheimer's disease
HUCBC 的意义:阿尔茨海默病的一种新治疗策略
- 批准号:
8305549 - 财政年份:2009
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Implication of HUCBC: a novel therapeutic strategy for Alzheimer's disease
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- 批准号:
8505320 - 财政年份:2009
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Statin modulation of immunotherapy for Alzheimer disease
他汀类药物调节阿尔茨海默病免疫疗法
- 批准号:
7681379 - 财政年份:2009
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