Mechanisms underlying the differential response to rosiglitazone of individuals with different ApoE genotypes

不同 ApoE 基因型个体对罗格列酮差异反应的机制

• 批准号: G0700653/1
• 负责人: Diane Hanger
• 金额: $ 54.79万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700653%2F1
• 关键词: Mechanisms; underlying; differential; response; rosiglitazone

Alzheimer?s disease (AD) is a very complex disorder for which there are few known risk factors. However it is known that advancing age increases the risk of developing AD as does possession of a particular type of a protein called apolipoprotein E (ApoE). ApoE occurs in three types (ApoE2, ApoE3, ApoE4) and possession of ApoE4 is associated with an increased risk of developing AD.One of the primary characteristic features of AD is the presence in the brain of clumps of a protein called amyloid beta-peptide (Abeta), the presence of which is thought to be detrimental to nerve cells. Abeta derives from a larger protein, called amyloid precursor protein (APP), from which Abeta is cut out. Cleavage of APP occurs primarily in the membranes of nerve cells, but in specific regions called ?lipid rafts? from where it is then exported to the outside of the cell to form the detrimental clumps containing Abeta.A drug that is used to treat diabetes (Avandia?), developed by GlaxoSmithKline, has recently been found to be useful for treating some people with AD. However, Avandia? was only beneficial for people carrying ApoE3 or ApoE2 and not ApoE4. The main functions of ApoE are to bind lipids and cholesterol and to transport them around the body. The different types of ApoE perform these functions with differing abilities but it is not known how this might relate to the differences in the observed therapeutic effects of Avandia? in AD sufferers. It is important therefore to try to understand how Avandia? is working so that better drugs can be developed.Our hypothesis is that the differential effects of Avandia? in AD patients may be related to differences in the ApoE forms that result in different (1) ability to remove Abeta from the brain or (2) sensitivity of nerve cells to the toxic effects of Abeta.Results that are of interest to the general public will be publicised on the MRC Centre for Neurodegeneration website and through reports in the associated bulletins as well as through press reports where appropriate.

老年痴呆症吗?阿尔茨海默病（AD）是一种非常复杂的疾病，已知的危险因素很少。然而，众所周知，年龄增长会增加患阿尔茨海默病的风险，因为拥有一种叫做载脂蛋白E （ApoE）的特殊蛋白质也会增加患阿尔茨海默病的风险。ApoE存在于三种类型（ApoE2, ApoE3, ApoE4），拥有ApoE4与患AD的风险增加有关。阿尔茨海默病的主要特征之一是大脑中存在一种叫做淀粉样蛋白-肽（Abeta）的蛋白质团块，这种蛋白质的存在被认为对神经细胞有害。β来源于一种更大的蛋白质，叫做淀粉样前体蛋白（APP），而β则是从APP中切割出来的。APP的切割主要发生在神经细胞的细胞膜上，但也发生在被称为？脂质筏?然后从那里输出到细胞外部，形成含有β的有害团块。葛兰素史克公司（GlaxoSmithKline）开发的一种用于治疗糖尿病的药物（文迪雅？）最近被发现对治疗某些AD患者有用。然而,文迪雅吗?只对携带ApoE3或ApoE2的人有益，而对携带ApoE4的人无效。载脂蛋白e的主要功能是结合脂质和胆固醇，并将它们运输到全身。不同类型的ApoE以不同的能力执行这些功能，但尚不清楚这与观察到的文迪雅治疗效果的差异有何关系？在阿尔茨海默病患者中因此，理解文迪雅是如何？正在发挥作用，以便开发出更好的药物。我们的假设是文迪雅的不同效果？可能与ApoE形式的差异有关，ApoE形式导致(1)从大脑中去除Abeta的能力不同，或(2)神经细胞对Abeta毒性作用的敏感性不同。公众感兴趣的结果将在MRC神经变性中心网站上公布，并通过相关公报的报道以及适当的新闻报道进行公布。