文章基本信息

标题：Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane
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作者：Hebah Fatafta ; Mohammed Khaled ; Michael C. Owen 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：39
DOI：10.1073/pnas.2106210118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance The aggregation of the amyloid- β peptide (A β ) into neurotoxic oligomers is central to the development of Alzheimer’s disease. One possible source of their toxicity results from interactions of the A β oligomers with the neuronal membrane, damaging membrane integrity and thus neurons. However, molecular details of these interactions are unclear. Here, we contrast the dimerization of A β in solution and at the neuronal membrane. Our results clearly indicate that the sugar moieties of GM1 sequester A β by forming key hydrogen bonds with the peptide, which diverts the configuration of the A β dimers away from damaging β -sheet–rich structures. These findings underline the importance of GM1 in Alzheimer’s disease progression and provide a nanoscopic basis for its reported neuroprotective effect. Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity of amyloid- β peptides in Alzheimer’s disease. To gain a detailed understanding of the mutual interference of amyloid- β oligomers and the neuronal membrane, we carried out microseconds of all-atom molecular dynamics (MD) simulations on the dimerization of amyloid- β (A β )42 in the aqueous phase and in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. 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 A β 42 dimer by attenuating its propensity to form a β -sheet structure. The main lipid interaction partners of A β 42 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 A β -mediated toxicity.
关键词：enAlzheimer’s disease;amyloid-β;neuronal membrane;molecular dynamics;transition network