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@ARTICLE{Dawkins:257785,
      author       = {Dawkins, Edgar and Derks, Rico J E and Schifferer, Martina
                      and Trambauer, Johannes and Winkler, Edith and Simons,
                      Mikael and Paquet, Dominik and Giera, Martin and Kamp, Frits
                      and Steiner, Harald},
      title        = {{M}embrane lipid remodeling modulates γ-secretase
                      processivity.},
      journal      = {The journal of biological chemistry},
      volume       = {299},
      number       = {4},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {DZNE-2023-00500},
      pages        = {103027},
      year         = {2023},
      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.},
      keywords     = {Humans / Amyloid Precursor Protein Secretases: genetics /
                      Amyloid Precursor Protein Secretases: metabolism / Membrane
                      Lipids: metabolism / Amyloid beta-Peptides: metabolism /
                      Alzheimer Disease: genetics / Alzheimer Disease: metabolism
                      / Cell Line / Amyloid beta-Protein Precursor: metabolism /
                      Presenilin-1: metabolism / Aβ37/38 (Other) / Alzheimer
                      disease (Other) / Aβ37/38 (Other) / amyloid precursor
                      protein (APP) processing (Other) / amyloid-β peptide (Aβ)
                      (Other) / erucic acid (Other) / lipid homeostasis (Other) /
                      lipidomics (Other) / membrane thickness (Other) / presenilin
                      (Other) / γ-secretase (Other) / Amyloid Precursor Protein
                      Secretases (NLM Chemicals) / Membrane Lipids (NLM Chemicals)
                      / Amyloid beta-Peptides (NLM Chemicals) / Amyloid
                      beta-Protein Precursor (NLM Chemicals) / Presenilin-1 (NLM
                      Chemicals) / amyloid-β peptide (Aβ) (Other) / γ-secretase
                      (Other)},
      cin          = {AG Steiner / AG Misgeld / AG Simons},
      ddc          = {540},
      cid          = {I:(DE-2719)1110000-1 / I:(DE-2719)1110000-4 /
                      I:(DE-2719)1110008},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36805335},
      pmc          = {pmc:PMC10070668},
      doi          = {10.1016/j.jbc.2023.103027},
      url          = {https://pub.dzne.de/record/257785},
}