Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado 80309, United States.
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, United States.
J Phys Chem Lett. 2020 Sep 3;11(17):7417-7422. doi: 10.1021/acs.jpclett.0c02074. Epub 2020 Aug 25.
While many approaches to reduce fibrillation of amyloid-β (Aβ) have been aimed at slowing fibril formation, the degradation of fibrils remains challenging. We provide insight into fibril degradation as well as the inhibition of fiber formation by lipid vesicles composed of 1,2-dioleoyl--glycero-3-phosphocholine and 1,2-dioleoyl--glycero-3-phospho-(1'-rac-glycerol). In the presence of vesicles with the optimal lipid composition, fibril formation was inhibited up to 76%. Additionally, by tuning the lipid composition, mature fibril content decreased up to 74% and the β-sheet content of Aβ was significantly reduced. The reduction in fibril and β-sheet content was consistent with a decrease in fibril diameter and could be attributed to the chaperone-like activity of the mixed vesicles. While demonstrating this remarkable activity, our findings present new evidence that lipid composition has a significant effect on the strength of the interaction between lipid bilayers and Aβ peptides/fibrils. This understanding has intriguing therapeutic implications in treating protein misfolding diseases.
虽然许多减少淀粉样蛋白-β（Aβ）纤维形成的方法都旨在减缓纤维的形成，但纤维的降解仍然具有挑战性。我们深入研究了纤维的降解以及由 1,2-二油酰基-sn-甘油-3-磷酸胆碱和 1,2-二油酰基-sn-甘油-3-磷酸-(1'-rac-甘油)组成的脂质体对纤维形成的抑制作用。在具有最佳脂质组成的囊泡存在的情况下，纤维形成被抑制了高达 76%。此外，通过调整脂质组成，成熟纤维的含量降低了高达 74%，并且 Aβ 的β-折叠含量显著降低。纤维和β-折叠含量的降低与纤维直径的减小一致，这归因于混合囊泡的伴侣样活性。虽然证明了这种显著的活性，但我们的研究结果提供了新的证据，表明脂质组成对脂双层与 Aβ 肽/纤维之间相互作用的强度有显著影响。这一认识在治疗蛋白质错误折叠疾病方面具有有趣的治疗意义。
