权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Modulation of Alzheimer-associated gamma-secretase by the lipid environment

脂质环境对阿尔茨海默病相关γ-分泌酶的调节

基本信息

批准号：
321765742
负责人：
Professor Dr. Harald Steiner
金额：
--
依托单位：
Lehrstuhl für Stoffwechselbiochemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/321765742?language=en
关键词：
Modulation Alzheimer associated gamma secretase

项目摘要

According to current knowledge, Alzheimer´s disease (AD) develops as a consequence of an accumulation of amyloid beta-peptide (Abeta), a small pathogenic peptide in the brain of affected patients. Abeta is generated by sequential proteolytic cleavage of the beta-amyloid precursor protein (APP) by the lipid membrane-associated beta- and gamma-secretase. The latter intramembrane-cleaving protease executes the final step in Abeta generation. Changes in the brain lipid metabolism known to occur in AD impact on Abeta generation by the secretases. With this research proposal, we want to get a better understanding of how gamma-secretase is modulated by its lipid environment and to obtain insight into the underlying mechanisms. The focus of our research project will lie on the study of the membrane surface charge, a crucial parameter of the properties of lipid membranes. Based on encouraging, robust preliminary data, we will in the first part of the project analyze how changes of the membrane surface charge impact on gamma-secretase, in particular with respect to the generation of the pathogenic Abeta species, Abeta 42/43, in model membranes and living cells including neurons. In the second part of the project, we will study the underlying mechanism(s). In particular, we will investigate, how the conformation of gamma-secretase will change in response to alterations of membrane surface charge. By these studies, our research project will contribute to a better understanding of the mode of action of gamma-secretase, a pivotal intramembrane protease and AD drug target.

根据目前的知识，阿尔茨海默病（AD）的发展是淀粉样β肽（Abeta）积累的结果，Abeta是一种小的致病肽在受影响的患者的大脑中。 Abeta是通过脂质膜相关β-和γ-分泌酶对β-淀粉样前体蛋白（APP）的连续蛋白水解裂解产生的。后一种膜内切割蛋白酶执行Abeta生成的最后一步。已知在AD中发生的脑脂质代谢的变化影响分泌酶产生的Abeta。通过这项研究计划，我们希望更好地了解γ-分泌酶如何受到其脂质环境的调节，并深入了解其潜在机制。我们研究项目的重点将在于膜表面电荷的研究，这是脂质膜性质的一个关键参数。基于令人鼓舞的，强大的初步数据，我们将在该项目的第一部分分析膜表面电荷的变化如何影响γ-分泌酶，特别是在模型膜和活细胞（包括神经元）中致病性Abeta物种Abeta 42/43的产生方面。在项目的第二部分，我们将研究潜在的机制。特别是，我们将调查，如何γ-分泌酶的构象将改变响应于膜表面电荷的改变。通过这些研究，我们的研究项目将有助于更好地了解γ-分泌酶，一个关键的膜内蛋白酶和AD药物靶点的作用方式。