Drolle E, Kučerka N, Hoopes M I, Choi Y, Katsaras J, Karttunen M, Leonenko Z
Department of Biology, University of Waterloo, Canada.
Biochim Biophys Acta. 2013 Sep;1828(9):2247-54. doi: 10.1016/j.bbamem.2013.05.015. Epub 2013 May 25.
The cell membrane plays an important role in the molecular mechanism of amyloid toxicity associated with Alzheimer's disease. The membrane's chemical composition and the incorporation of small molecules, such as melatonin and cholesterol, can alter its structure and physical properties, thereby affecting its interaction with amyloid peptides. Both melatonin and cholesterol have been recently linked to amyloid toxicity. Melatonin has been shown to have a protective role against amyloid toxicity. However, the underlying molecular mechanism of this protection is still not well understood, and cholesterol's role remains controversial. We used small-angle neutron diffraction (SAND) from oriented lipid multi-layers, small-angle neutron scattering (SANS) from unilamellar vesicles experiments and Molecular Dynamics (MD) simulations to elucidate non-specific interactions of melatonin and cholesterol with 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) model membranes. We conclude that melatonin decreases the thickness of both model membranes by disordering the lipid hydrocarbon chains, thus increasing membrane fluidity. This result is in stark contrast to the much accepted ordering effect induced by cholesterol, which causes membranes to thicken.
细胞膜在与阿尔茨海默病相关的淀粉样蛋白毒性分子机制中起着重要作用。膜的化学成分以及诸如褪黑素和胆固醇等小分子的掺入，能够改变其结构和物理性质，进而影响其与淀粉样肽的相互作用。褪黑素和胆固醇最近都与淀粉样蛋白毒性相关联。已表明褪黑素对淀粉样蛋白毒性具有保护作用。然而，这种保护作用的潜在分子机制仍未得到充分理解，并且胆固醇的作用仍存在争议。我们利用来自取向脂质多层膜的小角中子衍射（SAND）、来自单层囊泡实验的小角中子散射（SANS）以及分子动力学（MD）模拟，来阐明褪黑素和胆固醇与1,2 - 二油酰 - sn - 甘油 - 3 - 磷酸胆碱（DOPC）和1,2 - 二棕榈酰 - sn - 甘油 - 3 - 磷酸胆碱（DPPC）模型膜的非特异性相互作用。我们得出结论，褪黑素通过扰乱脂质烃链来降低两种模型膜的厚度，从而增加膜的流动性。这一结果与胆固醇所引起的被广泛接受的有序化效应形成鲜明对比，胆固醇会导致膜变厚。
