Kengwerere Maurine K, Kenyaga June M, Xiao Peng, Gunaga Shubha S, Scott Faith J, Wutoh-Hughes Xyomara, Wang James, Lum Brian, Sun Yan, Mentink-Vigier Frederic, Wang Tuo, Qiang Wei
Department of Chemistry, Binghamton University, State University of New York, Binghamton, NY, USA.
Department of Chemistry, Michigan State University, East Lansing, MI, USA.
Commun Chem. 2025 Apr 30;8(1):131. doi: 10.1038/s42004-025-01537-8.
Non-specific disruption of cellular membranes induced by amyloidogenic aggregation of β-amyloid (Aβ) peptides remains a viable cytotoxicity mechanism in Alzheimer's disease (AD). Obtaining structural information about the intermediate states of Aβ-membrane systems and their molecular interactions is challenging due to their heterogeneity and low abundance. Here, we systematically study the molecular interactions of membrane-associated Aβ peptides using solid-state nuclear magnetic resonance (ssNMR) spectroscopy, focusing on the primary nucleation phase of the fibrillation process. Compared to the less pathogenic Aβ peptide, Aβ forms smaller oligomers prior to fibrillation, as evidenced by a higher overall population of lipid-proximity peptides. Aβ also exhibits more pronounced residue-specific contacts with phospholipid headgroups compared to Aβ, with multiple lipid-proximity segments throughout the entire primary sequence. The segments involved in initial inter-strand assembly overlap with those located near the lipid headgroups in Aβ, whereas these two segments are distinct in Aβ. ssNMR spectroscopy with sensitivity enhanced by Dynamic nuclear polarization (DNP) confirmed local secondary structural convergence during the nucleation process of Aβ and the presence of long-range tertiary contacts at early stages of nucleation. Overall, our results provide a molecular-level understanding of the Aβ nucleation process in a membrane-like environment and its membrane-disrupting intermediates. The comparison between Aβ and Aβ explains its higher cytotoxicity from the perspective of membrane disruption.
β-淀粉样蛋白（Aβ）肽的淀粉样生成聚集所诱导的细胞膜非特异性破坏仍然是阿尔茨海默病（AD）中一种可行的细胞毒性机制。由于Aβ-膜系统的异质性和低丰度，获取其中间状态及其分子相互作用的结构信息具有挑战性。在这里，我们使用固态核磁共振（ssNMR）光谱系统地研究了膜相关Aβ肽的分子相互作用，重点关注纤维化过程的初级成核阶段。与致病性较低的Aβ肽相比，Aβ在纤维化之前形成更小的寡聚体，这表现为与脂质接近的肽的总体数量更高。与Aβ相比，Aβ与磷脂头部基团的残基特异性接触也更明显，在整个一级序列中有多个与脂质接近的片段。参与初始链间组装的片段与Aβ中位于脂质头部基团附近的片段重叠，而这两个片段在Aβ中是不同的。通过动态核极化（DNP）增强灵敏度的ssNMR光谱证实了Aβ成核过程中的局部二级结构收敛以及成核早期远程三级接触的存在。总体而言，我们的结果提供了对膜样环境中Aβ成核过程及其膜破坏中间体的分子水平理解。Aβ与Aβ的比较从膜破坏的角度解释了其更高的细胞毒性。
