Center for Biomedical Engineering , University of New Mexico , Albuquerque , New Mexico 87131 , United States.
Department of Chemical and Biological Engineering , University of New Mexico , Albuquerque , New Mexico 87131 , United States.
Langmuir. 2019 Dec 3;35(48):16024-16036. doi: 10.1021/acs.langmuir.9b02484. Epub 2019 Sep 26.
In Alzheimer's disease, the amyloid-beta peptide (Aβ) is implicated in neuronal toxicity via interactions with the cell membrane. Monomeric Aβ (Aβ) is intrinsically disordered, but it can adopt a range of aggregated conformations with varying toxicities from short fibrillar oligomers (FO), to globular nonfibrillar oligomers (NFO), and full-length amyloid fibrils. NFO is considered to be the most toxic, followed by fibrils, and finally Aβ. To elucidate molecular-level membrane interactions that contribute to their different toxicities, we used liquid surface X-ray scattering and Langmuir trough insertion assays to compare Aβ, FO, and NFO surface activities and interactions with anionic DMPG lipid monolayers at the air/water interface. All Aβ species were highly surface active and rapidly adopted β-sheet rich structures upon adsorption to the air/water interface. Likewise, all Aβ species had affinity for the anionic membrane. Aβ rapidly converted to β-sheet rich assemblies upon binding the membrane, and these aggregated structures of Aβ and FO disrupted hexagonally packed lipid domains and resulted in membrane thinning and instability. In contrast, NFO perturbed membrane structure by extracting lipids from the air/water interface and causing macroscale membrane deformations. Altogether, our results support two models for membrane-mediated Aβ toxicity: fibril-induced reorganization of lipid packing and NFO-induced membrane destabilization and lipid extraction. This work provides a structural understanding of Aβ neurotoxicity via membrane interactions and aids the effort in understanding early events in Alzheimer's disease and other neurodegenerative diseases.
在阿尔茨海默病中,淀粉样β肽(Aβ)通过与细胞膜相互作用而导致神经元毒性。单体 Aβ(Aβ)本质上是无定形的,但它可以采用一系列具有不同毒性的聚集构象,从短纤维状寡聚物(FO)到球状无纤维状寡聚物(NFO),再到全长淀粉样纤维。NFO 被认为是最具毒性的,其次是纤维,最后是 Aβ。为了阐明导致其不同毒性的分子水平的膜相互作用,我们使用液-面 X 射线散射和 Langmuir 槽插入测定法,比较了 Aβ、FO 和 NFO 的表面活性及其与阴离子 DMPG 脂质单层在气/水界面的相互作用。所有 Aβ 物种都具有很高的表面活性,并在吸附到气/水界面时迅速形成富含β-折叠的结构。同样,所有 Aβ 物种都对阴离子膜具有亲和力。Aβ 在结合膜时迅速转化为富含β-折叠的组装体,这些 Aβ 和 FO 的聚集结构破坏了六方排列的脂质域,并导致膜变薄和不稳定。相比之下,NFO 通过从气/水界面提取脂质并引起宏观膜变形来扰乱膜结构。总之,我们的结果支持两种通过膜相互作用介导 Aβ 毒性的模型:纤维诱导的脂质堆积重组和 NFO 诱导的膜不稳定和脂质提取。这项工作通过膜相互作用提供了对 Aβ 神经毒性的结构理解,并有助于理解阿尔茨海默病和其他神经退行性疾病的早期事件。