Nicastrin and Presenilin-dependent gamma-secretase

尼卡斯特林和早老素依赖性γ-分泌酶

• 批准号: 6837687
• 负责人: PHILIP C WONG
• 金额: $ 38.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837687
• 关键词: Nicastrin; Presenilin; dependent; gamma; secretase

EXCEED THE SPACE PROVIDED. Alzheimer's disease (AD), a progressive neurodegenerative disorder of the elderly, is characterized by the deposition of 13-amyloid (AI_) and neurofibriUary tangles in the hippocampus and cerebral cortex. Endoproteolytic cleavages of amyloid precursor protein (APP) by _-and ?- secretases result in the generation of AI3 peptides that are believed to be neurotoxic. The presenilins (PS1 and PS2), which when mutated cause familial AD, are important for the intramembraneous proteolysis of several proteins, including APP and Notch1. The presenilins is part of a high molecular weight complex that contains the ?-secretase. Critical to this 7-secretase complex is another type I transmembrane glycoprotein, termed nicastrin that binds to both APP and Notch1 and is required for glp-l/notch signaling. Recent studies in nicastrin-deficient Drosophila demonstrate that the loss of nicastrin abolishes the presenilin-dependent intramembraneous proteolysis of Notch. Thus, we hypothesize that nicastrin is required for proteolytic processing and signaling of Notch1 in mammals. We plan first to determine whether reduced levels of nicastrin impact on presenilin-mediated Notch signaling in mammals by generating nicastrin.deficient mice and characterize the phenotypic consequences of reduction in nicastrin. Secondly, because studies indicated that nicastdn plays an important role in APP processing, we will test the role of nicastrin in presenilin-mediated 7-secretase cleavage of APP using nicastrin knockout cells. In addition, we will determine the mechanism whereby nicastrin influences presenilins to facilitate transmembrane cleavage of Notch and APP. Finally, to examine the in vivo role of nicastrin in adult brain, we will generate and characterize nicastrin conditional knockout mice. Taken together, outcomes from these efforts will have important implications toward our understanding of the mechanism whereby nicastrin influences presenilins in facilitating the presenilin-dependent 7-secretase activities on several critical pathways, including Notch and APP, as well as for nicastrin as a potential therapeutic target in AD. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。阿尔茨海默病（AD）是一种进行性老年人神经退行性疾病，其特征是海马和大脑皮层中13-淀粉样蛋白（AI_）和神经纤维缠结的沉积。淀粉样蛋白前体蛋白（APP）被_和？分泌酶导致AI3肽的产生，被认为是神经毒性的。早老素（PS1和PS2）在发生突变时会导致家族性AD，它对包括APP和Notch1在内的几种蛋白的膜内蛋白水解很重要。早老素是含有-分泌酶的高分子量复合物的一部分。7-分泌酶复合体的关键是另一种I型跨膜糖蛋白，称为nicastrin，它与APP和Notch1结合，是glp- 1 /notch信号传导所必需的。最近对nicastrin缺乏的果蝇的研究表明，nicastrin的缺失消除了Notch的早老素依赖的膜内蛋白水解。因此，我们假设nicastrin是哺乳动物Notch1蛋白水解加工和信号传导所必需的。我们计划首先通过产生nicastrin缺陷小鼠来确定nicastrin水平降低是否会影响哺乳动物早老素介导的Notch信号传导，并表征nicastrin减少的表型后果。其次，由于研究表明nicastdn在APP加工过程中发挥重要作用，我们将使用nicastrin敲除细胞来测试nicastrin在早老素介导的7-secretase切割APP中的作用。此外，我们将确定nicastrin影响早老素促进Notch和APP跨膜切割的机制。最后，为了检验nicastrin在成人大脑中的体内作用，我们将产生nicastrin条件敲除小鼠并对其进行表征。综上所述，这些努力的结果将对我们理解nicastrin影响早老素的机制具有重要意义，该机制促进了早老素依赖的7-分泌酶在几个关键通路上的活性，包括Notch和APP，以及nicastrin作为AD的潜在治疗靶点。网站性能 ======================================== 节结束 ===========================================