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

点击翻译按钮获取中文摘要

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.