Solution NMR Studies of the Aβ(1-40) and Aβ(1-42) Peptides Establish that the Met35 Oxidation State Affects the Mechanism of Amyloid Formation

Liming Hou, Haiyan Shao, Yongbo Zhang, Hua Li, Nanda K. Menon, Elizabeth B. Neuhaus, John M. Brewer, In Ja L. Byeon, Dale G. Ray, Michael P. Vitek, Takashi Iwashita, Ronald A. Makula, Alan B. Przybyla, Michael G. Zagorski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

476 Scopus citations


The pathogenesis of Alzheimer's disease is characterized by the aggregation and fibrillation of the 40-residue Aβ(1-40) and 42-residue Aβ(1-42) peptides into amyloid plaques. The structural changes associated with the conversion of monomeric Aβ peptide building blocks into multimeric fibrillar β-strand aggregates remain unknown. Recently, we established that oxidation of the methionine-35 side chain to the sulfoxide (Met35red → Met35ox) significantly impedes the rate of aggregation and fibrillation of the Aβ peptide. To explore this effect at greater resolution, we carefully compared the 1H, 15N, and 13C NMR chemical shifts of four Aβ peptides that had the Met35 reduced or oxidized (Aβ(1-40)Met35red, Aβ(1-40)Met35ox, Aβ(1-42)Met35red, and Aβ(1-42)Met35ox). With the use of a special disaggregation protocol, the highly aggregation prone Aβ peptides could be studied at higher, millimolar concentrations (as required by NMR) in aqueous solution at neutral pH, remaining largely monomeric at 5 °C as determined by sedimentation equilibrium studies. The NOE, amide-NH temperature coefficients, and chemical shift indices of the 1Hα, 13Cα, and 13Cβ established that the four peptides are largely random, extended chain structures, with the Met35ox reducing the propensity for β-strand structure at two hydrophobic regions (Leu17-Ala21 and Ile31-Val36), and turn- or bendlike structures at Asp7-Glu11 and Phe20-Ser26. Additional NMR studies monitoring changes that occur during aging at 37 °C established that, along with a gradual loss of signal/noise, the Met35 ox significantly hindered upfield chemical shift movements of the 2H NMR signals for the His6, His13, and His14 side chains. Taken together, the present NMR studies demonstrate that the Met35red → Met35 ox conversion prevents aggregation by reducing both hydrophobic and electrostatic association and that the Aβ(1-40)Met35red, Aβ(1-40)Met35ox, Aβ(1-42)Met35red, and Aβ(1-42)Met35ox peptides may associate differently, through specific, sharp changes in structure during the initial stages of aggregation.

Original languageEnglish (US)
Pages (from-to)1992-2005
Number of pages14
JournalJournal of the American Chemical Society
Issue number7
StatePublished - Feb 25 2004

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry


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