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

根据目前的知识，阿尔茨海默病（AD）的发展是淀粉样蛋白β肽（Abeta）积累的结果，Abeta是受影响患者大脑中的一种小致病肽。β是由脂质膜相关的β和γ分泌酶对β -淀粉样前体蛋白（APP）进行连续的蛋白水解裂解而产生的。后一种膜内切割蛋白酶执行β生成的最后一步。已知AD中发生的脑脂质代谢变化对分泌酶生成β的影响。通过这项研究计划，我们希望更好地了解γ -分泌酶是如何被其脂质环境调节的，并深入了解其潜在机制。我们的研究项目将重点放在膜表面电荷的研究上，这是脂质膜性质的一个关键参数。基于令人鼓舞的、可靠的初步数据，我们将在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，特别是关于模型膜和活细胞（包括神经元）中致病性Abeta物种Abeta 42/43的产生。在项目的第二部分，我们将研究潜在的机制。特别是，我们将研究-分泌酶的构象如何随着膜表面电荷的改变而改变。通过这些研究，我们的研究项目将有助于更好地了解-分泌酶的作用模式，这是一种关键的膜内蛋白酶和AD药物靶点。

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.