Amyloid-βpeptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity of amyloidβ-peptides in Alzheimer’s disease. This study aims at gaining detailed understanding of the mutual interference of amyloid-β oligomers and the neuronal membrane, which is extremely difficult to capture experimentally due to the transient nature of these interactions. To address this problem we use an aggregate of 24μs of MD simulations to investigate the dimerization of the full-length Aβ42 peptide both in solution and in the presence of a model lipid bilayer including six lipid types to mimick the composition of a neuronal cell membrane: 38% 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 24%, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 5% 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS), 20% cholesterol (CHOL), 9% sphingomyelin (SM), and 4% monosialotetrahexosylgan-glioside (GM1).
The dimerization in solution is characterized by a random coil to β-sheet transition that seems on-pathway to amyloid aggregation, while the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. As the neurotoxic activity of amyloid oligomers increases with oligomer order, these results suggest that GM1 is neuroprotective against Aβ-mediated toxicity.

越来越多的证据表明，神经元细胞膜是阿尔茨海默病中淀粉样β肽寡聚体介导神经元毒性的主要作用位点。本研究旨在深入解析淀粉样β（amyloid-β, Aβ）寡聚体与神经元细胞膜之间的相互作用——由于这类相互作用具有瞬时性，通过实验手段捕捉该过程极具挑战性。为解决这一难题，我们依托总时长达24微秒的分子动力学（MD, Molecular Dynamics）模拟，分别探究了全长Aβ42肽在纯溶液中，以及在包含六种脂质以模拟神经元细胞膜组分的模型脂质双层膜环境中的二聚化过程：该脂质双层的组分为38%的1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱（1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, POPC）、24%的1-棕榈酰-2-油酰-sn-甘油-3-磷酸乙醇胺（1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine, POPE）、5%的1-棕榈酰-2-油酰-sn-甘油-3-磷酸-L-丝氨酸（1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine, POPS）、20%的胆固醇（cholesterol, CHOL）、9%的鞘磷脂（sphingomyelin, SM）以及4%的单唾液酸四己糖神经节苷脂（monosialotetrahexosylganglioside, GM1）。纯溶液中的Aβ42二聚化过程以无规卷曲向β折叠的转变为特征，该过程似乎是淀粉样蛋白聚集的必经通路；而与神经元细胞膜的相互作用则会降低Aβ42二聚体的有序性，削弱其形成β折叠结构的倾向。Aβ42的主要脂质结合伴侣为神经节苷脂GM1暴露于膜表面的糖基基团。鉴于淀粉样寡聚体的神经毒性随寡聚体有序性升高而增强，本研究结果表明GM1可对Aβ介导的神经毒性发挥神经保护作用。