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001     257785
005     20240112171729.0
024 7 _ |a 10.1016/j.jbc.2023.103027
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024 7 _ |a pmid:36805335
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024 7 _ |a pmc:PMC10070668
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024 7 _ |a 0021-9258
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024 7 _ |a 1067-8816
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024 7 _ |a 1083-351X
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024 7 _ |a altmetric:142887638
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037 _ _ |a DZNE-2023-00500
041 _ _ |a English
082 _ _ |a 540
100 1 _ |a Dawkins, Edgar
|b 0
245 _ _ |a Membrane lipid remodeling modulates γ-secretase processivity.
260 _ _ |a Bethesda, Md.
|c 2023
|b Soc.
336 7 _ |a article
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520 _ _ |a 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.
536 _ _ |a 352 - Disease Mechanisms (POF4-352)
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650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: genetics
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: metabolism
|2 MeSH
650 _ 2 |a Membrane Lipids: metabolism
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: metabolism
|2 MeSH
650 _ 2 |a Alzheimer Disease: genetics
|2 MeSH
650 _ 2 |a Alzheimer Disease: metabolism
|2 MeSH
650 _ 2 |a Cell Line
|2 MeSH
650 _ 2 |a Amyloid beta-Protein Precursor: metabolism
|2 MeSH
650 _ 2 |a Presenilin-1: metabolism
|2 MeSH
650 _ 7 |a Aβ37/38
|2 Other
650 _ 7 |a Alzheimer disease
|2 Other
650 _ 7 |a Aβ37/38
|2 Other
650 _ 7 |a amyloid precursor protein (APP) processing
|2 Other
650 _ 7 |a amyloid-β peptide (Aβ)
|2 Other
650 _ 7 |a erucic acid
|2 Other
650 _ 7 |a lipid homeostasis
|2 Other
650 _ 7 |a lipidomics
|2 Other
650 _ 7 |a membrane thickness
|2 Other
650 _ 7 |a presenilin
|2 Other
650 _ 7 |a γ-secretase
|2 Other
650 _ 7 |a Amyloid Precursor Protein Secretases
|0 EC 3.4.-
|2 NLM Chemicals
650 _ 7 |a Membrane Lipids
|2 NLM Chemicals
650 _ 7 |a Amyloid beta-Peptides
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650 _ 7 |a Amyloid beta-Protein Precursor
|2 NLM Chemicals
650 _ 7 |a Presenilin-1
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650 _ 7 |a amyloid-β peptide (Aβ)
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650 _ 7 |a γ-secretase
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700 1 _ |a Derks, Rico J E
|b 1
700 1 _ |a Schifferer, Martina
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700 1 _ |a Trambauer, Johannes
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700 1 _ |a Winkler, Edith
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700 1 _ |a Simons, Mikael
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700 1 _ |a Paquet, Dominik
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700 1 _ |a Giera, Martin
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700 1 _ |a Kamp, Frits
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700 1 _ |a Steiner, Harald
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773 _ _ |a 10.1016/j.jbc.2023.103027
|g Vol. 299, no. 4, p. 103027 -
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|t The journal of biological chemistry
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|y 2023
|x 0021-9258
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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