how cholesterol constrains glycolipid conformation for optimal recognition of alzheimers β amyloid peptide (aβ1-40)胆固醇如何约束醣脂类构造最优识别阿尔茨海默氏症的β淀粉样肽(aβ1-40).pdfVIP

How Cholesterol Constrains Glycolipid Conformation for Optimal Recognition of Alzheimer’s b Amyloid Peptide (Ab1-40) ¨ ¤ Nouara Yahi, Anaıs Aulas , Jacques Fantini* ´ ´ ´ ´ ´ Universite Paul Cezanne (Aix-Marseille 3), Universite de la Mediterranee (Aix-Marseille 2), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, CNRS ´ ` ´ ´ ˆ UMR 6231, INRA USC 2027, Interactions Moleculaires et Systemes Membranaires, Faculte des Sciences Saint-Jerome, Marseille, France Abstract Membrane lipids play a pivotal role in the pathogenesis of Alzheimer’s disease, which is associated with conformational changes, oligomerization and/or aggregation of Alzheimer’s b-amyloid (Ab) peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs) on the supramolecular assembly of Ab peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Ab1–40 and chemically defined GSLs (GalCer, LacCer, GM1, GM3). Using the Langmuir monolayer technique, we show that Ab1–40 selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs). In contrast, Ab1–40 did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs). Cholesterol inhibited the interaction of Ab1–40 with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Ab1–40 binding. Both crystallographic data and molecular dynamics simulations sug