Membrane lipid remodeling modulates γ-secretase processivity

Journal of Biological Chemistry, vol. 299, pp. 103027

Abstract

Imbalances in the amounts of amyloid-β peptides (Aβ) generated by the membrane proteases β- and γ-secretase are considered as a trigger of Alzheimer's disease (AD). Cell-free studies of γ-secretase have shown that increasing membrane thickness modulates Aβ generation but it has remained unclear if these effects are translatable to cells. Here we show that the very long-chain fatty acid erucic acid (EA) triggers acyl chain remodeling in AD cell models, resulting in substantial lipidome alterations which included increased esterification of EA in membrane lipids. Membrane remodeling enhanced γ-secretase processivity, resulting in the increased production of the potentially beneficial Aβ37 and/or Aβ38 species in multiple cell lines. Unexpectedly, we found that the membrane remodeling stimulated total Aβ secretion by cells expressing WT γ-secretase but lowered it for cells expressing an aggressive familial AD mutant γ-secretase. We conclude that EA-mediated modulation of membrane composition is accompanied by complex lipid homeostatic changes that can impact amyloidogenic processing in different ways and elicit distinct γ-secretase responses, providing critical implications for lipid-based AD treatment strategies.

Authors 10

1. Edgar Dawkins

   Ludwig-Maximilians-Universität München

   Affiliation as printed

   Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center (BMC), LMU Munich, Munich, Germany

2. Rico J. E. Derks Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics & Metabolomics, Leiden University Medical Center (LUMC), Leiden, The Netherlands

3. Martina Schifferer

   German Center for Neurodegenerative Diseases · Munich Cluster for Systems Neurology

   Affiliation as printed

   German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany

   German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

   Munich Cluster of Systems Neurology (SyNergy), Munich, Germany

4. Johannes Trambauer

   Ludwig-Maximilians-Universität München

   Affiliation as printed

   Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center (BMC), LMU Munich, Munich, Germany

5. Edith Winkler

   Ludwig-Maximilians-Universität München

   Affiliation as printed

   Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center (BMC), LMU Munich, Munich, Germany

6. Mikael Simons

   German Center for Neurodegenerative Diseases · Munich Cluster for Systems Neurology · Technical University of Munich

   Affiliation as printed

   German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany; Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany

   German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

   Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany

   Munich Cluster of Systems Neurology (SyNergy), Munich, Germany

7. Dominik Paquet

   Munich Cluster for Systems Neurology · Institut für Schlaganfall- und Demenzforschung · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Munich Cluster of Systems Neurology (SyNergy), Munich, Germany; Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany

   Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany

   Munich Cluster of Systems Neurology (SyNergy), Munich, Germany

8. Martin A. Giera Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics & Metabolomics, Leiden University Medical Center (LUMC), Leiden, The Netherlands

9. Frits Kamp

   Ludwig-Maximilians-Universität München

   Affiliation as printed

   Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center (BMC), LMU Munich, Munich, Germany

10. Harald Steiner corresponding

    German Center for Neurodegenerative Diseases · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center (BMC), LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Electronic address: harald.steiner@med.uni-muenchen.de

    Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center (BMC), LMU Munich, Munich, Germany

    German Center for Neurodegenerative Diseases (DZNE), Munich, Germany