Alzheimer’s disease (AD) patients could benefit from a more effective treatment than the current FDA-approved options. Because amyloid-beta (Aβ) is thought to play a central role in AD pathogenesis, many experimental drugs attempt to reduce Aβ-induced pathology. Preventing amyloid accumulation may be a more effective strategy than clearing Aβ plaques after they form. If preventing Aβ accumulation can treat or prevent AD, then understanding Aβ primary nucleation may aid rational drug design. This study examines Aβ residue interaction networks and reports network and structural observations that may provide insight into primary nucleation. While many studies identify structural features of Aβ that promote aggregation, this study reports features that may resist primary nucleation by examining Aβ42 studies in more and less polar solvents. In Aβ42 in a less polar solvent (PDB ID: 1IYT), Val24 and Ile31 have higher betweenness and residue centrality values. This may be due to a predicted interaction between Val24 and Ile31. Residues in the central hydrophobic cluster (CHC) of Aβ40 and Aβ42 had significantly higher betweenness values compared to the average betweenness of the structures, highlighting the CHC’s reported role in oligomerization. The predicted interaction between Val24 and Ile31 may reduce the likelihood of primary nucleation of Aβ.

阿尔茨海默病 (AD) 患者可以从比目前 FDA 批准的选择更有效的治疗中受益。由于淀粉样蛋白-β (Aβ) 被认为在 AD 发病机制中起核心作用，因此许多实验性药物试图减少 Aβ 诱导的病理。预防淀粉样蛋白积聚可能是比在 Aβ 斑块形成​​后清除它们更有效的策略。如果阻止 Aβ 积累可以治疗或预防 AD，那么了解 Aβ 初级成核可能有助于合理的药物设计。这项研究检查了 Aβ 残基相互作用网络，并报告了网络和结构观察，这些观察可能有助于深入了解初级成核。虽然许多研究确定了 Aβ 促进聚集的结构特征，但本研究报告了通过检查极性不同的溶剂中的 Aβ42 研究可能抵抗初级成核的特征。在极性较小的溶剂 (PDB ID: 1IYT) 中的 Aβ42 中，Val24 和 Ile31 具有更高的介数和残基中心值。这可能是由于 Val24 和 Ile31 之间的预测相互作用。与结构的平均介数相比，Aβ40 和 Aβ42 的中央疏水簇 (CHC) 中的残基具有显着更高的介数值，突出了 CHC 在低聚化中的作用。Val24 和 Ile31 之间的预测相互作用可能会降低 Aβ 初级成核的可能性。强调了 CHC 在低聚化中的作用。Val24 和 Ile31 之间的预测相互作用可能会降低 Aβ 初级成核的可能性。强调了 CHC 在低聚化中的作用。Val24 和 Ile31 之间的预测相互作用可能会降低 Aβ 初级成核的可能性。