Membrane lipid remodeling modulates γ-secretase processivity

Edgar Dawkins, Rico J.E. Derks, Martina Schifferer, Johannes Trambauer, Edith Winkler, Mikael Simons, Dominik Paquet, Martin Giera, Frits Kamp, Harald Steiner

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Article number103027
JournalJournal of Biological Chemistry
Volume299
Issue number4
DOIs
StatePublished - Apr 2023
Externally publishedYes

Keywords

  • Alzheimer disease
  • Aβ37/38
  • amyloid precursor protein (APP) processing
  • amyloid-β peptide (Aβ)
  • erucic acid
  • lipid homeostasis
  • lipidomics
  • membrane thickness
  • presenilin
  • γ-secretase

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