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: 7151155
• 负责人: PHILIP C WONG
• 金额: $ 36.82万
• 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/7151155
• 关键词: Adenoviruses; Adult; Alleles; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Amyloidosis; Binding; Biology; Brain; Caenorhabditis elegans; Cathepsins B; Cell surface; Cells; Cerebral cortex; Co-Immunoprecipitations; Complex; Critical Pathways; Deposition; Development; Drosophila genus; Elderly; Embryo; Generations; Genes; Glycoproteins; Hippocampus (Brain); Human; Knock-out; Knockout Mice; Length; Mammalian Cell; Mammals; Mediating; Membrane; Molecular Weight; Mus; Mutate; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Outcome; Pathway interactions; Peptides; Play; Process; Prosencephalon; Proteins; Proteolysis; Proteolytic Processing; RNA Interference; Research; Research Personnel; Role; Signal Transduction; Standards of Weights and Measures; Testing; Thinking; Variant; amyloid precursor protein processing; base; beta-site APP cleaving enzyme 1; design; embryonic stem cell; familial Alzheimer disease; gamma secretase; in vivo; neurotoxic; nicastrin protein; notch protein; presenilin; programs; research study; secretase; therapeutic target; trafficking

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.

老年痴呆症（AD）是一种进行性神经退行性疾病

项目成果

Specific domains in anterior pharynx-defective 1 determine its intramembrane interactions with nicastrin and presenilin.

• DOI: 10.1016/j.neurobiolaging.2009.12.028
• 发表时间: 2012-02
• 期刊: NEUROBIOLOGY OF AGING
• 影响因子: 4.2
• 作者: Chiang, Po-Min;Fortna, Ryan R.;Price, Donald L.;Li, Tong;Wong, Philip C.
• 通讯作者: Wong, Philip C.

Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals.

尼卡斯特林是组装早老素/γ-分泌酶复合物以介导Notch信号传导以及哺乳动物中β-淀粉样前体蛋白的加工和运输所必需的。

• DOI: 10.1523/jneurosci.23-08-03272.2003
• 发表时间: 2003
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Li,Tong;Ma,Guojun;Cai,Huaibin;Price,DonaldL;Wong,PhilipC
• 通讯作者: Wong,PhilipC