Institute of Physical Biology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany.
Institute of Biological Information Processing, IBI-7: Structural Biochemistry, Forschungszentrum Jülich, D-52428 Jülich, Germany.
J Phys Chem Lett. 2023 Feb 16;14(6):1427-1435. doi: 10.1021/acs.jpclett.2c03729. Epub 2023 Feb 3.
Amyloid-beta (Aβ) deposition as senile plaques is a pathological hallmark of Alzheimer's disease (AD). AD is characterized by a large level of heterogeneity in amyloid pathology, whose molecular origin is poorly understood. Here, we employ NMR spectroscopy and MD simulation at ambient and high pressures and investigate how AD-related mutations in Aβ peptide influence the stability of Aβ aggregates. The pressure-induced monomer dissociation from Aβ aggregates monitored by NMR demonstrated that the Iowa (D23N), Arctic (E22G), and Osaka (ΔE22) mutations altered the pressure stability of Aβ40 aggregates in distinct manners. While the NMR data of monomeric Aβ40 showed only small localized effects of mutations, the MD simulation of mutated Aβ fibrils revealed their distinct susceptibility to elevated pressure. Our data propose a structural basis for the distinct stability of various Aβ fibrils and highlights "stability" as a molecular property potentially contributing to the large heterogeneity of amyloid pathology in AD.
淀粉样蛋白-β（Aβ）沉积形成老年斑是阿尔茨海默病（AD）的病理标志。AD 的淀粉样蛋白病理学具有很大程度的异质性，其分子起源尚不清楚。在这里，我们采用 NMR 光谱和环境和高压下的 MD 模拟，研究 AD 相关 Aβ肽突变如何影响 Aβ聚集体的稳定性。通过 NMR 监测的压力诱导单体从 Aβ聚集体中解离表明，爱荷华州（D23N）、北极（E22G）和大阪（ΔE22）突变以不同的方式改变了 Aβ40 聚集体的压力稳定性。虽然 NMR 数据显示单体 Aβ40 只有突变的小局部影响，但突变 Aβ原纤维的 MD 模拟显示它们对高压有不同的敏感性。我们的数据为各种 Aβ原纤维的不同稳定性提供了结构基础，并强调了“稳定性”作为一个潜在有助于 AD 中淀粉样蛋白病理学的大异质性的分子特性。
