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

根据目前的知识，阿尔茨海默病(AD)的发生是由于患者大脑中淀粉样β-肽(Abeta)的积聚，这是一种小的致病多肽。Abeta是由脂膜相关的β-和γ-分泌酶对β-淀粉样前体蛋白(APP)进行连续的蛋白分解而产生的。后一种膜内裂解酶执行Abeta生成的最后一步。已知在AD中发生的脑脂代谢的变化通过分泌酶影响Abeta的产生。通过这项研究建议，我们想要更好地了解伽马分泌酶是如何受到其脂质环境的调节的，并对其潜在的机制进行深入的了解。我们的研究项目的重点将放在膜表面电荷的研究上，膜表面电荷是脂膜性能的关键参数。基于令人鼓舞的、稳健的初步数据，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伽马分泌酶，特别是在模型膜和包括神经元在内的活细胞中产生致病的Abeta物种Abet42/43方面。在项目的第二部分，我们将研究其背后的机制(S)。特别是，我们将研究伽马分泌酶的构象如何随着膜表面电荷的变化而变化。通过这些研究，我们的研究项目将有助于更好地理解膜内关键酶和AD药物靶点--γ-分泌酶的作用机制。

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.