Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
Monash Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton/Melbourne, VIC 3800, Australia.
J Phys Chem Lett. 2024 Jun 20;15(24):6292-6298. doi: 10.1021/acs.jpclett.4c01048. Epub 2024 Jun 10.
The interaction of small Amyloid-β (Aβ) oligomers with the lipid membrane is an important component of the pathomechanism of Alzheimer's disease (AD). However, oligomers are heterogeneous in size. How each type of oligomer incorporates into the membrane, and how that relates to their toxicity, is unknown. Here, we employ a single molecule technique called Q-SLIP (Quencher-induced Step Length Increase in Photobleaching) to measure the membrane insertion of each monomeric unit of individual oligomers of Aβ42, Aβ40, and Aβ40-F19-Cyclohexyl alanine (Aβ40-F19Cha), and correlate it with their toxicity. We observe that the N-terminus of Aβ42 inserts close to the center of the bilayer, the less toxic Aβ40 inserts to a shallower depth, and the least toxic Aβ40-F19Cha has no specific distribution. This oligomer-specific map provides a mechanistic representation of membrane-mediated Aβ toxicity and should be a valuable tool for AD research.
小淀粉样蛋白-β（Aβ）寡聚物与脂膜的相互作用是阿尔茨海默病（AD）发病机制的重要组成部分。然而，寡聚物在大小上是不均匀的。每种类型的寡聚物如何融入膜中，以及这与它们的毒性有何关系，目前尚不清楚。在这里，我们采用一种称为 Q-SLIP（淬灭诱导的光漂白中步长增加）的单分子技术来测量 Aβ42、Aβ40 和 Aβ40-F19-环己基丙氨酸（Aβ40-F19Cha）的各个寡聚物的每个单体单元插入膜的情况，并将其与它们的毒性相关联。我们观察到 Aβ42 的 N 端插入靠近双层的中心，毒性较小的 Aβ40 插入的深度较浅，毒性最小的 Aβ40-F19Cha 没有特定的分布。这种寡聚体特异性图谱提供了一种膜介导的 Aβ 毒性的机制表示，应该是 AD 研究的有价值的工具。
