Amyloid β-protein (Aβ) assembly is a seminal process in Alzheimer’s disease. Elucidating the mechanistic features of this process is thought to be vital for the design and targeting of therapeutic agents. Computational studies of the most pathologic form of Aβ, the 42-residue Aβ42 peptide, have suggested that hydrogen bonding involving Ser26 may be particularly important in organizing a monomer folding nucleus and in subsequent peptide assembly. To study this question, we experimentally determined structure–activity relationships among Aβ42 peptides in which Ser26 was replaced with Gly, Ala, α-aminobutryic acid (Abu), or Cys. We observed that aliphatic substitutions (Ala and Abu) produced substantially increased rates of formation of β-sheet, hydrophobic surface, and fibrils, and higher levels of cellular toxicity. Replacement of the Ser hydroxyl group with a sulfhydryl moiety (Cys) did not have these effects. Instead, this peptide behaved like native Aβ42, even though the hydropathy of Cys was similar to that of Abu and very different from that of Ser. We conclude that H bonding of Ser26 is the factor most important in its contribution to Aβ42 conformation, assembly, and subsequent toxicity.

中文翻译：

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Ser26氢键在Aβ42组装和毒性中的关键作用

β淀粉样蛋白（Aβ）组装是阿尔茨海默氏病的一个精巢过程。阐明该过程的机械特征被认为对于治疗剂的设计和靶向至关重要。对Aβ最病理形式的42个残基的Aβ42肽的计算研究表明，涉及Ser26的氢键在组织单体折叠核和随后的肽组装中可能特别重要。为了研究这个问题，我们通过实验确定了其中Ser26被Gly，Ala，α-氨基丁酸（Abu）或Cys取代的Aβ42肽之间的构效关系。我们观察到脂族取代基（Ala和Abu）产生的β-折叠，疏水性表面和原纤维的形成速率大大提高，并且细胞毒性水平更高。用巯基部分（Cys）取代Ser羟基没有这些作用。相反，即使Cys的亲水性与Abu的亲水性和Ser的亲水性非常不同，该肽的行为也像天然的Aβ42。我们得出结论，Ser26的H键是其对Aβ42构象，组装和后续毒性的最重要因素。