We studied the interactions of a tau derived hexapeptide AcPHF6 with β-amyloid peptides Aβ40 and Aβ42 which reveals its unusual ability to promote Aβ fibrillogenesis. The results demonstrate that the N-acetylated and C-amidated AcPHF6 hexapeptide can cause significant acceleration in Aβ40 and Aβ42 fibril growth. Aggregation kinetic studies at pH 7.4 show that at 25 μM, AcPHF6 hexapeptide was able to cause ∼2.3-fold increase in Aβ40 fibrillogenesis dramatically changing the aggregation kinetics. In addition, AcPHF6 peptide was able to reduce cellular toxicity mediated by Aβ40 and Aβ42 in hippocampal neuronal cell line (HT22). Computational studies suggest that the AcPHF6 peptide can act as an anchor and provides a hydrophobic surface for Aβ monomer to bind and undergo rapid fibrillogenesis to form less toxic fibrils and alter the aggregation kinetics. At the molecular level we propose a “dock-and-pack” mechanism where the AcPHF6 hexapeptide aggregates can stabilize the β-hairpin and promote rapid Aβ self-assembly and growth to form less toxic oligomers or fibrils. Our results have direct implications in designing novel peptide/peptidomimetics as novel pharmacological tools to study protein aggregation and potentially prevent Aβ-mediated toxicity in Alzheimer’s disease.

中文翻译：

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Tau衍生的六肽AcPHF6促进β-淀粉样蛋白（Aβ）的原纤维形成。

我们研究了tau衍生的六肽AcPHF6与β-淀粉样肽Aβ40和Aβ42的相互作用，揭示了其促进Aβ原纤维形成的异常能力。结果表明，N-乙酰化和C酰胺化的AcPHF6六肽可显着促进Aβ40和Aβ42的原纤维生长。在pH 7.4时的聚集动力学研究表明，在25μM时，AcPHF6六肽能够引起Aβ40原纤维形成增加约2.3倍，从而显着改变聚集动力学。另外，AcPHF6肽能够减少海马神经元细胞系（HT22）中由Aβ40和Aβ42介导的细胞毒性。计算研究表明，AcPHF6肽可以充当锚，并为Aβ单体提供疏水表面，使其结合并快速发生原纤维形成，从而形成毒性较小的原纤维并改变聚集动力学。在分子水平上，我们提出了一种“码头装箱”机制，其中AcPHF6六肽聚集体可以稳定β-发夹并促进快速的Aβ自组装和生长，从而形成毒性较小的低聚物或原纤维。我们的结果对设计新型肽/拟肽作为研究药物聚集并潜在预防Aβ介导的阿尔茨海默氏病毒性的新型药理学工具具有直接的启示。