Toprakcioglu Zenon, Jayaram Akhila K, Knowles Tuomas P J
Yusuf Hamied Department of Chemistry, University of Cambridge Lensfield Road Cambridge CB2 1EW UK
Cavendish Laboratory, Department of Physics, University of Cambridge J J Thomson Avenue Cambridge CB3 0HE UK.
RSC Chem Biol. 2025 Mar 13;6(5):809-822. doi: 10.1039/d4cb00189c. eCollection 2025 May 8.
The aggregation of the amyloid-β (Aβ) peptides (Aβ42/Aβ40) into amyloid fibrils and plaques is one of the molecular hallmarks in dementia and Alzheimer's disease (AD). While the molecular mechanisms behind this aggregation process are not fully known, it has been shown that some biomolecules can accelerate this process whereas others can inhibit amyloid formation. Lipids, which are ubiquitously found in cell membranes, play a pivotal role in protein aggregation. Here, we investigate how ganglioside lipids, which are abundant in the brain and in neurons, can influence the aggregation kinetics of both Aβ42 and Aβ40. We employ a variety of biophysical assays to characterise the effect ganglioside lipids have on the aggregation of Aβ. Through kinetic analysis, we show that the primary nucleation rate is greatly affected by the addition of gangliosides and that these lipids impair Aβ42 aggregation, while completely inhibiting Aβ40 aggregation. Furthermore, we find that an Aβ-ganglioside complex is formed, which potentially disrupts the aggregation pathway and results in delayed kinetics. Taken together, our results provide a quantitative description of how lipid molecules such as gangliosides can inhibit the aggregation of Aβ and shed light on the key factors that control these processes. In view of the fact that declining levels of gangliosides in neurons have been associated with ageing, our findings could be instrumental towards establishing new approaches in the prevention of amyloid-β aggregation.
淀粉样β（Aβ）肽（Aβ42/Aβ40）聚集成淀粉样原纤维和斑块是痴呆症和阿尔茨海默病（AD）的分子标志之一。虽然这一聚集过程背后的分子机制尚不完全清楚，但已表明一些生物分子可加速这一过程，而其他一些生物分子则可抑制淀粉样蛋白的形成。普遍存在于细胞膜中的脂质在蛋白质聚集中起关键作用。在此，我们研究在大脑和神经元中含量丰富的神经节苷脂如何影响Aβ42和Aβ40的聚集动力学。我们采用多种生物物理分析方法来表征神经节苷脂对Aβ聚集的影响。通过动力学分析，我们表明初级成核速率受神经节苷脂添加的极大影响，并且这些脂质会损害Aβ42的聚集，同时完全抑制Aβ40的聚集。此外，我们发现形成了一种Aβ - 神经节苷脂复合物，它可能会破坏聚集途径并导致动力学延迟。综上所述，我们的结果提供了关于神经节苷脂等脂质分子如何抑制Aβ聚集的定量描述，并揭示了控制这些过程的关键因素。鉴于神经元中神经节苷脂水平下降与衰老有关，我们的发现可能有助于建立预防淀粉样β聚集的新方法。
