Feuillie Cecile, Lambert Eleonore, Ewald Maxime, Azouz Mehdi, Henry Sarah, Marsaudon Sophie, Cullin Christophe, Lecomte Sophie, Molinari Michael
CBMN, CNRS UMR 5248, IPB, Université de Bordeaux, Pessac, France.
LRN EA 4682, Université de Reims Champagne-Ardenne, Reims, France.
Front Mol Biosci. 2020 Sep 9;7:571696. doi: 10.3389/fmolb.2020.571696. eCollection 2020.
Due to an aging population, neurodegenerative diseases such as Alzheimer's disease (AD) have become a major health issue. In the case of AD, Aβ peptides have been identified as one of the markers of the disease with the formation of senile plaques via their aggregation, and could play a role in memory impairment and other tragic syndromes associated with the disease. Many studies have shown that not only the morphology and structure of Aβ peptide assembly are playing an important role in the formation of amyloid plaques, but also the interactions between Aβ and the cellular membrane are crucial regarding the aggregation processes and toxicity of the amyloid peptides. Despite the increasing amount of information on AD associated amyloids and their toxicity, the molecular mechanisms involved still remain unclear and require in-depth investigation at the local scale to clearly decipher the role of the sequence of the amyloid peptides, of their secondary structures, of their oligomeric states, and of their interactions with lipid membranes. In this original study, through the use of Atomic Force Microscopy (AFM) related-techniques, high-speed AFM and nanoInfrared AFM, we tried to unravel at the nanoscale the link between aggregation state, structure and interaction with membranes in the amyloid/membrane interaction. Using three mutants of Aβ peptides, L34T, oG37C, and WT Aβ peptides, with differences in morphology, structure and assembly process, as well as model lipidic membranes whose composition and structure allow interactions with the peptides, our AFM study coupling high spatial and temporal resolution and nanoscale structure information clearly evidences a local correlation between the secondary structure of the peptides, their fibrillization kinetics and their interactions with model membranes. Membrane disruption is associated to small transient oligomeric entities in the early stages of aggregation that strongly interact with the membrane, and present an antiparallel β-sheet secondary structure. The strong effect on membrane integrity that exists when these oligomeric Aβ peptides interact with membranes of a particular composition could be a lead for therapeutic studies.
由于人口老龄化，诸如阿尔茨海默病（AD）等神经退行性疾病已成为一个重大的健康问题。就AD而言，Aβ肽已被确定为该疾病的标志物之一，其通过聚集形成老年斑，并可能在记忆障碍及与该疾病相关的其他悲惨综合征中起作用。许多研究表明，不仅Aβ肽组装体的形态和结构在淀粉样斑块的形成中起重要作用，而且Aβ与细胞膜之间的相互作用对于淀粉样肽的聚集过程和毒性也至关重要。尽管关于AD相关淀粉样蛋白及其毒性的信息越来越多，但所涉及的分子机制仍不清楚，需要在局部尺度上进行深入研究，以清楚地解读淀粉样肽的序列、二级结构、寡聚状态及其与脂质膜相互作用的作用。在这项原创研究中，通过使用与原子力显微镜（AFM）相关的技术，即高速AFM和纳米红外AFM，我们试图在纳米尺度上揭示淀粉样蛋白/膜相互作用中聚集状态、结构与膜相互作用之间的联系。使用三种Aβ肽突变体L34T、oG37C和野生型Aβ肽，它们在形态、结构和组装过程上存在差异，以及使用其组成和结构允许与肽相互作用的模型脂质膜，我们的AFM研究结合了高空间和时间分辨率以及纳米尺度结构信息，清楚地证明了肽的二级结构、纤维化动力学及其与模型膜相互作用之间的局部相关性。膜破坏与聚集早期的小瞬态寡聚实体相关，这些实体与膜强烈相互作用，并呈现反平行β-折叠二级结构。当这些寡聚Aβ肽与特定组成的膜相互作用时，对膜完整性存在的强烈影响可能是治疗研究的一个线索。
