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

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

8 Zitate (Scopus)

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.

OriginalspracheEnglisch
Aufsatznummer103027
FachzeitschriftJournal of Biological Chemistry
Jahrgang299
Ausgabenummer4
DOIs
PublikationsstatusVeröffentlicht - Apr. 2023
Extern publiziertJa

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