Protein-Protein Interactions in the Biology of Beta-APP

Beta-APP 生物学中的蛋白质-蛋白质相互作用

• 批准号: 8124900
• 负责人: DENNIS J SELKOE
• 金额: $ 32.52万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124900
• 关键词: Address; Adherent Culture; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animal Model; Attention; Biological; Biology; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain region; Cell Surface Receptors; Cell membrane; Cellular biology; Cerebrum; Complex; Conflict (Psychology); Cytopathology; Data; Defect; Disease; Endocytosis; Engineering; Epithelial; Future; Gene Transfer Techniques; Genetic; Genetic Models; Grant; Herpesvirus Type 3; Human; In Vitro; Inherited; Insulin; Insulinase; Knock-out; Knowledge; Laboratories; Late Onset Alzheimer Disease; Left; Life; Literature; Mediating; Membrane Protein Traffic; Memory; Metalloproteases; Minority; Molecular; Mutagenesis; Mutation; Neprilysin; Peptide Hydrolases; Peptides; Peripheral; Primates; Production; Proteins; Proteolysis; RNA Interference; Research Personnel; Role; Scientist; Structure-Activity Relationship; Therapeutic; Thinking; Time; Work; age related; association cortex; base; biochemical model; brain cell; design; extracellular; fascinate; in vitro Model; in vivo; in vivo Model; insertion/deletion mutation; islet amyloid polypeptide; knock-down; mild neurocognitive impairment; mouse model; novel therapeutic intervention; presenilin; presenilin-1; prevent; protein protein interaction; protein transport; receptor; research study; secretase

DESCRIPTION (provided by applicant): Studies from many laboratories now generally support the amyloid (or Abeta) hypothesis of Alzheimer's disease (AD), and therapeutic trails based on this concept have begun. Nevertheless, we are left with many unresolved and fascinating biological questions about how a small hydrophobic peptide slowly accumulates in the brain with age and can apparently initiate cytopathology. Perhaps foremost among these questions is exactly why cerebral Abeta levels are elevated in humans who develop AD. Increased Abeta production appears to explain only a small minority of cases, principally those inheriting mutations in APP or the presenilins. This realization suggests that many, perhaps most, cases of AD are caused by faulty clearance of a peptide that is produced at normal levels throughout life. Our proposed work here is based on 3 related hypotheses: 1) defects in proteases which degrade Abeta may underlie some or many cases of familial and sporadic late-onset AD; 2) non-proteolytic clearance mechanisms (e.g., receptor-mediated efflux through the blood brain barrier) could explain the rise in cerebral Abeta in other cases; and 3) whether or not these two mechanisms are actually causative, subtly activating such proteases or else stimulating protein transport mechanisms could lower cerebral Abeta levels therapeutically. To extend our productive work under this grant on both the basic and applied aspects of this understudied subject, we propose 3 aims: Aim 1: To determine whether central or peripheral expression of engineered versions of two well-characterized Abeta degrading proteases - neprilysin and insulin degrading enzyme (IDE) -can safely and effectively decrease cerebral Abeta burden in mouse models of AD. Aim 2: In view of the recent unequivocal demonstration that IDE exists normally on the plasma membrane (namely, as the receptor for varicella-zoster virus), to further ellucidate the unusual cell biology and membrane trafficking of IDE that enables it to be involved in the degradation of both extracellular/intraluminal substrates (e.g., Abeta, insulin, amylin) and cytoplasmic substrates (e.g., AICD). Aim 3: To pursue a recently initiated project that addresses an even less well-studied aspect of Abeta clearance than proteolysis, namely, to rigorously identify and validate the cell- surface receptors capable of mediating the efflux of soluble Abeta across the BBB, using both in vitro and in vivo models. Understanding how both proteolysis and non-proteolytic clearance regulate Abeta levels in the brain has major implications for both the genesis and treatment of this complex disorder. At the same time, the proposed experiments have fundamental implications for peptide turnover in the mammalian brain and for the cell biology of metalloproteases. Many scientists now support the idea that the gradual buildup of a small protein, amyloid beta-protein (Abeta), in brain regions serving memory and thinking causes Alzheimer's disease. This grant will examine exactly why this buildup occurs over time, focusing on two potential problems: 1) faulty cutting up of the Abeta protein in the brain; or 2) faulty transport of the Abeta protein from the brain into the circulation. We will also explore new ways to increase the cutting up or the transport of Abeta as future therapeutic approaches for preventing Alzheimer's disease.

描述（由申请人提供）：许多实验室的研究现在通常支持阿尔茨海默氏病（AD）的淀粉样蛋白（或ABETA）假设，以及基于此概念的治疗痕迹。然而，我们剩下许多尚未解决和引人入胜的生物学问题，即小疏水肽如何随着年龄的增长而慢慢积聚，并且显然可以启动细胞病理学。在这些问题中，也许最重要的是为什么发展广告的人类脑abeta级别的含量会提高。 ABETA产量增加似乎仅解释了少数病例，主要是在APP或Presenilins中遗传突变的病例。这种认识表明，许多AD的病例可能是由于对肽在整个生命中以正常水平产生的肽的清除有错误的清除而引起的。我们在这里提出的工作基于3个相关假设：1）蛋白酶的缺陷降解了Abeta可能是一些或多个家族性和零星后的晚期AD的基础； 2）非蛋白溶解清除机制（例如受体介导的流体通过血脑屏障）可以解释其他情况下脑ABETA的上升； 3）这两种机制是否实际上是病因，巧妙地激活此类蛋白酶，或者刺激蛋白质转运机制可以降低脑Abeta治疗水平。为了将我们的生产性工作扩展到这项经过研究的主题的基本和应用方面，我们提出了3个目标：目的1：确定两个特征良好的ABETA降解蛋白酶的工程版本的中心或外围表达是neprilysin和胰岛素降解酶（iDE）的模型（iDe）的模型，并有效地降低了bur的模型，以实现bur的模型。 Aim 2: In view of the recent unequivocal demonstration that IDE exists normally on the plasma membrane (namely, as the receptor for varicella-zoster virus), to further ellucidate the unusual cell biology and membrane trafficking of IDE that enables it to be involved in the degradation of both extracellular/intraluminal substrates (e.g., Abeta, insulin, amylin) and细胞质底物（例如AICD）。 目标3：追求一个最近发起的项目，该项目解决了与蛋白水解相比，要解决abeta清除率更少的方面，即严格地识别和验证能够使用体外和体内模型的细胞表面受体介导整个BBB的可溶性ABETA外排的细胞表面受体。了解蛋白水解和非蛋白水解清除率如何调节大脑中的Abeta水平对这种复杂疾病的起源和治疗都具有重大影响。同时，提出的实验对哺乳动物大脑的肽离职和金属蛋白酶细胞生物学具有根本性。现在，许多科学家都支持这样一种观念，即在脑部地区逐渐积聚了小蛋白质淀粉样蛋白β-蛋白质（ABETA），这会导致阿尔茨海默氏病。该赠款将准确地研究这种积累会随着时间的流逝而发生的原因，重点是两个潜在的问题：1）切割大脑中Abeta蛋白的故障；或2）ABETA蛋白从大脑转移到循环系统的错误转运。作为预防阿尔茨海默氏病的未来治疗方法，我们还将探讨增加Abeta切割或运输的新方法。