Department of Chemistry, Binghamton University, State University of New York, Binghamton, New York 13902, United States.
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States.
ACS Chem Neurosci. 2023 Dec 6;14(23):4153-4162. doi: 10.1021/acschemneuro.3c00523. Epub 2023 Nov 22.
Co-aggregation involving different amyloidogenic sequences has been emphasized recently in the modified amyloid cascade hypothesis. Yet, molecular-level interactions between two predominant β-amyloid peptide sequences, Aβ and Aβ, in the fibrillation process in membrane-mimicked environments remain unclear. Here, we report biophysical evidence that demonstrates the molecular-level interactions between Aβ and Aβ at the membrane-associated conucleation stage using dynamic nuclear polarization-enhanced solid-state NMR spectroscopy. These residue-specific contacts are distinguished from those reported in mature fibrils formed by either Aβ or Aβ. Meanwhile, site-specific interactions between Aβ and lipid molecules and modulation of microsecond-time-scale lipid dynamics are observed, which may be responsible for the more rapid and significant membrane content leakage compared to that with Aβ alone.
最近在改良的淀粉样蛋白级联假说中强调了涉及不同淀粉样蛋白序列的共聚集。然而，在膜模拟环境中的纤维化过程中，两种主要的β-淀粉样肽序列 Aβ和 Aβ 之间的分子水平相互作用仍不清楚。在这里，我们使用动态核极化增强固态 NMR 光谱学报告了生物物理证据，证明了在与膜相关的共成核阶段 Aβ 和 Aβ 之间的分子水平相互作用。这些残基特异性接触与在由 Aβ 或 Aβ 形成的成熟纤维中报道的接触不同。同时，观察到 Aβ 和脂质分子之间的位点特异性相互作用以及微秒时间尺度上的脂质动力学的调制，这可能是与单独使用 Aβ 相比，导致更快和更显著的膜内容物泄漏的原因。
