2023-05-04 ミュンヘン大学(LMU)
◆バイオメディカルセンターミュンヘンのハラルド・シュタイナー教授とエドガー・ドーキンス博士率いるチームは、細胞膜の厚みがアミロイドβの生成に影響を与えることを示しました。
◆彼らは、細胞膜のリモデリングが酵素活性を変化させ、アミロイドβの生成量を増加または減少させることができることを発見しました。これは、アルツハイマー病の治療戦略に新たな示唆を与える可能性があると考えられます。
<関連情報>
- https://www.lmu.de/en/newsroom/news-overview/news/alzheimers-modulation-of-cell-membrane-influences-formation-of-amyloid-%CE%B2.html
- https://www.jbc.org/article/S0021-9258(23)00159-X/fulltext
膜脂質リモデリングがγセクレターゼのプロセッシビティを調節する
Membrane lipid remodeling modulates γ-secretase processivity
Edgar Dawkins,Rico J.E. Derks,Martina Schifferer,Johannes Trambauer,Edith Winkler,Mikael Simons,Dominik Paquet,Martin Giera,Frits Kamp,Harald Steiner
Journal of Biological Chemistry Received: April 26, 2022
DOI:https://doi.org/10.1016/j.jbc.2023.103027
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.
