Journal Article

DZNE-2023-00500

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Membrane lipid remodeling modulates γ-secretase processivity.

Dawkins, E. ; Derks, R. J. E. ; Schifferer, M.DZNE* ; Trambauer, J. ; Winkler, E. ; Simons, M.DZNE* ; Paquet, D.Extern* ; Giera, M. ; Kamp, F.Extern* ; Steiner, H. (Last author)DZNE*

2023
Soc. Bethesda, Md.

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Please use a persistent id in citations: doi:10.1016/j.jbc.2023.103027

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.

Keyword(s): Humans (MeSH) ; Amyloid Precursor Protein Secretases: genetics (MeSH) ; Amyloid Precursor Protein Secretases: metabolism (MeSH) ; Membrane Lipids: metabolism (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Cell Line (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Presenilin-1: metabolism (MeSH) ; Aβ37/38 ; Alzheimer disease ; Aβ37/38 ; amyloid precursor protein (APP) processing ; amyloid-β peptide (Aβ) ; erucic acid ; lipid homeostasis ; lipidomics ; membrane thickness ; presenilin ; γ-secretase ; Amyloid Precursor Protein Secretases ; Membrane Lipids ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Presenilin-1 ; amyloid-β peptide (Aβ) ; γ-secretase

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Contributing Institute(s):

1. Biochemistry of γ-Secretase (AG Steiner)
2. Neuronal Cell Biology (AG Misgeld)
3. Molecular Neurobiology (AG Simons)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2023

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