A Critical Role of Ser26 Hydrogen Bonding in Aβ42 Assembly and Toxicity

Abstract

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.

Aggregation Mechanism of Alzheimer’s Amyloid β-Peptide Mediated by α-Strand/α-Sheet Structure

“…This is in agreement with an earlier experimental study which reported that the G25P mutation not only inhibits the aggregation of Aβ 1-42 but also prevents the neurotoxicity induced by this peptide [36]. A number of previous studies have reported the significance of region 23-28 in Aβ fibril formation [28][29][30]. Accordingly, the α-strand structure formed by residues 24-26 may have substantial importance in Aβ aggregation.…”

“…This demonstrates the possibility of extension of the α-strand region 24-26 (VGS). Several studies have reported the importance of region 23-28 in Aβ fibril formation [28][29][30]. Accordingly, the occurrence of α-strand in region 24-26 may have substantial importance.…”