Selective modulation of Gamma-secretase processing through substrate binding

通过底物结合选择性调节伽马分泌酶加工

• 批准号: 8416366
• 负责人: THOMAS L KUKAR
• 金额: $ 22.85万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416366
• 关键词: Abeta synthesis; Adverse effects; Affect; Alzheimer' s Disease; Amino Acids; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anti-Inflammatory Agents; Binding; Biology; Brain; C-terminal; Chemicals; Chronic; Cleaved cell; Cognitive; Complex; Data; Dementia; Development; Dimerization; Drug Targeting; Elderly; Enzymes; Event; Failure; Future; Goals; Grant; Human; In Vitro; Investigation; Label; Laboratories; Lead; Link; Membrane; Molecular Biology; Mutation; Patients; Pattern; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase III Clinical Trials; Placebos; Positioning Attribute; Process; Production; Property; Protein Biochemistry; Protein C; Proteolysis; Publishing; Reporting; Research; Research Proposals; Signal Pathway; Signal Transduction; Site; Specificity; Testing; Therapeutic; Work; amyloid precursor protein processing; base; cognitive function; crosslink; design; enzyme activity; gamma secretase; improved; in vivo; inhibitor/antagonist; insight; next generation; notch protein; novel; presenilin; prevent; protective effect; research study; rho; secretase; small molecule

Numerous lines of evidence support the hypothesis that targeting A[342 is an ideal therapeutic strategy to prevent and/or treat Alzheimer's disease (AD), the major cause of dementia among the elderly. Chemicals called y-secretase modulators (GSMs), are being developed as AD therapeutics because they are able to selectively decrease Ap42. The first GSMs to be discovered were non-steroidal antiinflammatory drugs (NSAIDs), which lower Ap42 without inhibition of APP processing. As a whole GSMs minimally alter total Abeta production and instead shift where gamma-secretase cleaves Abeta. The mechanism of GSMs is still unknown although different explanations for their activity have been proposed including: 1) allosteric binding to y-secretase 2) inhibition of the Rho-ROCK signaling pathway 3) conformational changes in presenilin or 4) decreased dimerization of APP. We have recently discovered using novel GSM photoaffinity probes that these drugs do not label the y-secretase enzyme but instead modulate cleavage by binding to the substrate, APP. We hypothesize that binding of APP by GSMs shifts the position of APP-CTF in the membrane resulting in altered gamma-secretase cleavage. This hypothesis will be tested through the following specific aims: 1) investigate how substrate targeting by GSMs produces a shift in the cleavage pattern of Ap using a combination of molecular biology and protein biochemistry 2) determine the specificity of GSMs for affecting APP proteolysis by y-secretase in comparison to other substrates and 3) incorporate unnatural amino acids to study proteolysis of APPCTF by y-secretase. These studies will provide additional insight into how NSAIDs and other GSMs shift A(3 cleavage and how they exert their protective effects in vivo. This work will also guide future efforts to design more potent GSMs which will be useful as chemical probes for understanding the biology of ysecretase and as potential therapeutics for Alzheimer's disease.

大量证据支持以下假设：针对[342是理想的治疗策略 预防和/或治疗老年人痴呆症的主要原因（AD）。 称为Y-分泌酶调节剂（GSM）的化学物质正在作为AD疗法开发，因为它们 能够选择性地降低AP42。第一个被发现的GSM是非甾体抗炎 药物（NSAID），降低AP42而不抑制应用程序处理。整个GSM 最小的改变Abeta的总产量，而是在γ-分泌酶切割Abeta的情况下转移。这 GSM的机制仍然未知，尽管已经提出了对其活动的不同解释 包括：1）与Y-分泌酶的变构结合2）抑制Rho-Rock信号通路3） presenilin的构象变化或4）APP的二聚化降低。我们最近发现了 使用新颖的GSM光相位探针，这些药物不标记Y-分泌酶酶，而是标记 通过与基板App结合来调节切割。我们假设GSM对应用程序的绑定 移动APP-CTF在膜中的位置，导致γ-分泌酶裂解改变。这 假设将通过以下特定目的进行检验：1）研究底物的靶向 GSM通过分子生物学和 蛋白质生物化学2）确定GSM的特异性，用于影响Y-分泌酶在 与其他底物进行比较，3）结合不自然的氨基酸来研究APPCTF的蛋白水解 由Y-分泌酶。这些研究将提供有关NSAID和其他GSM如何变化的更多见解 一个（3乳清乳清以及它们如何在体内发挥保护作用。这项工作还将指导未来的努力 设计更有效的GSM，这将是理解Y蛋白酶生物学的化学探针 作为阿尔茨海默氏病的潜在治疗方法。