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000257785 0247_ $$2doi$$a10.1016/j.jbc.2023.103027
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000257785 1001_ $$aDawkins, Edgar$$b0
000257785 245__ $$aMembrane lipid remodeling modulates γ-secretase processivity.
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000257785 520__ $$aImbalances 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.
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000257785 650_2 $$2MeSH$$aHumans
000257785 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000257785 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism
000257785 650_2 $$2MeSH$$aMembrane Lipids: metabolism
000257785 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000257785 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000257785 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000257785 650_2 $$2MeSH$$aCell Line
000257785 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: metabolism
000257785 650_2 $$2MeSH$$aPresenilin-1: metabolism
000257785 650_7 $$2Other$$aAβ37/38
000257785 650_7 $$2Other$$aAlzheimer disease
000257785 650_7 $$2Other$$aAβ37/38
000257785 650_7 $$2Other$$aamyloid precursor protein (APP) processing
000257785 650_7 $$2Other$$aamyloid-β peptide (Aβ)
000257785 650_7 $$2Other$$aerucic acid
000257785 650_7 $$2Other$$alipid homeostasis
000257785 650_7 $$2Other$$alipidomics
000257785 650_7 $$2Other$$amembrane thickness
000257785 650_7 $$2Other$$apresenilin
000257785 650_7 $$2Other$$aγ-secretase
000257785 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000257785 650_7 $$2NLM Chemicals$$aMembrane Lipids
000257785 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000257785 650_7 $$2NLM Chemicals$$aAmyloid beta-Protein Precursor
000257785 650_7 $$2NLM Chemicals$$aPresenilin-1
000257785 650_7 $$2Other$$aamyloid-β peptide (Aβ)
000257785 650_7 $$2Other$$aγ-secretase
000257785 7001_ $$aDerks, Rico J E$$b1
000257785 7001_ $$0P:(DE-2719)2812260$$aSchifferer, Martina$$b2$$udzne
000257785 7001_ $$0P:(DE-HGF)0$$aTrambauer, Johannes$$b3
000257785 7001_ $$0P:(DE-HGF)0$$aWinkler, Edith$$b4
000257785 7001_ $$0P:(DE-2719)2811642$$aSimons, Mikael$$b5$$udzne
000257785 7001_ $$0P:(DE-2719)2010112$$aPaquet, Dominik$$b6$$udzne
000257785 7001_ $$aGiera, Martin$$b7
000257785 7001_ $$0P:(DE-2719)2812549$$aKamp, Frits$$b8$$udzne
000257785 7001_ $$0P:(DE-2719)2000023$$aSteiner, Harald$$b9$$eLast author$$udzne
000257785 773__ $$0PERI:(DE-600)1474604-9$$a10.1016/j.jbc.2023.103027$$gVol. 299, no. 4, p. 103027 -$$n4$$p103027$$tThe journal of biological chemistry$$v299$$x0021-9258$$y2023
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