Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
Department of Pediatrics and Department of Neurology, UCSF, San Francisco, CA, 94158, USA.
Sci Rep. 2017 Oct 3;7(1):12434. doi: 10.1038/s41598-017-10845-6.
Amyloid β-protein (Aβ) assembly is hypothesized to be a seminal neuropathologic event in Alzheimer's disease (AD). We used an unbiased D-amino acid substitution strategy to determine structure-assembly relationships of 76 different Aβ40 and Aβ42 peptides. We determined the effects of the substitutions on peptide oligomerization, secondary structure dynamics, fibril assembly dynamics, and fibril morphology. Our experiments revealed that the assembly of Aβ42 was more sensitive to chiral substitutions than was Aβ40 assembly. Substitutions at identical positions in the two peptides often, but not always, produced the same effects on assembly. Sites causing substantial effects in both Aβ40 and Aβ42 include His14, Gln15, Ala30, Ile31, Met35, and Val36. Sites whose effects were unique to Aβ40 include Lys16, Leu17, and Asn 27, whereas sites unique to Aβ42 include Phe20 and Ala21. These sites may be appropriate targets for therapeutic agents that inhibit or potentiate, respectively, these effects.
淀粉样 β-蛋白 (Aβ) 的组装被假设为阿尔茨海默病 (AD) 的主要神经病理学事件。我们使用了一种无偏的 D-氨基酸取代策略来确定 76 种不同的 Aβ40 和 Aβ42 肽的结构-组装关系。我们确定了取代对肽寡聚、二级结构动力学、纤维组装动力学和纤维形态的影响。我们的实验表明，Aβ42 的组装比 Aβ40 组装对手性取代更敏感。在两个肽中相同位置的取代通常（但不总是）对组装产生相同的影响。在 Aβ40 和 Aβ42 中都产生重大影响的位点包括 His14、Gln15、Ala30、Ile31、Met35 和 Val36。对 Aβ40 具有独特影响的位点包括 Lys16、Leu17 和 Asn27，而对 Aβ42 具有独特影响的位点包括 Phe20 和 Ala21。这些位点可能是抑制或增强这些效应的治疗剂的合适靶标。
