Membrane lipid remodeling modulates γ-secretase processivity

Imbalances in the amounts of amyloid-beta peptides (A beta) generated by the membrane proteases beta- and gamma-secretase are considered as a trigger of Alzheimer's disease (AD). Cell-free studies of gamma-secretase have shown that increasing membrane thickness modulates A beta 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 gamma-secretase processivity, resulting in the increased production of the potentially beneficial A beta 37 and/or A beta 38 species in multiple cell lines. Unexpectedly, we found that the membrane remodeling stimulated total A beta secretion by cells expressing WT gamma-secre-tase but lowered it for cells expressing an aggressive familial AD mutant gamma-secretase. We conclude that EA-mediated mod-ulation of membrane composition is accompanied by complex lipid homeostatic changes that can impact amyloidogenic processing in different ways and elicit distinct gamma-secretase re-sponses, providing critical implications for lipid-based AD treatment strategies.