TY  - JOUR
AU  - Dawkins, Edgar
AU  - Derks, Rico J E
AU  - Schifferer, Martina
AU  - Trambauer, Johannes
AU  - Winkler, Edith
AU  - Simons, Mikael
AU  - Paquet, Dominik
AU  - Giera, Martin
AU  - Kamp, Frits
AU  - Steiner, Harald
TI  - Membrane lipid remodeling modulates γ-secretase processivity.
JO  - The journal of biological chemistry
VL  - 299
IS  - 4
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.
M1  - DZNE-2023-00500
SP  - 103027
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Membrane Lipids: metabolism
KW  - Amyloid beta-Peptides: metabolism
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: metabolism
KW  - Cell Line
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Presenilin-1: metabolism
KW  - Aβ37/38 (Other)
KW  - Alzheimer disease (Other)
KW  - Aβ37/38 (Other)
KW  - amyloid precursor protein (APP) processing (Other)
KW  - amyloid-β peptide (Aβ) (Other)
KW  - erucic acid (Other)
KW  - lipid homeostasis (Other)
KW  - lipidomics (Other)
KW  - membrane thickness (Other)
KW  - presenilin (Other)
KW  - γ-secretase (Other)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Membrane Lipids (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Presenilin-1 (NLM Chemicals)
KW  - amyloid-β peptide (Aβ) (Other)
KW  - γ-secretase (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36805335
C2  - pmc:PMC10070668
DO  - DOI:10.1016/j.jbc.2023.103027
UR  - https://pub.dzne.de/record/257785
ER  -