Early Divergence in Misfolding Pathways of Amyloid-Beta Peptides

Chemphyschem. 2021 Nov 4;22(21):2158-2163. doi: 10.1002/cphc.202100542. Epub 2021 Aug 19.


The amyloid cascade hypothesis proposes that amyloid-beta (Aβ) aggregation is the initial triggering event in Alzheimer's disease. Here, we utilize NMR spectroscopy and monitor the structural dynamics of two variants of Aβ, Aβ40 and Aβ42, as a function of temperature. Despite having identical amino acid sequence except for the two additional C-terminal residues, Aβ42 has higher aggregation propensity than Aβ40. As revealed by the NMR data on dynamics, including backbone chemical shifts, intra-methyl cross-correlated relaxation rates and glycine-based singlet-states, the C-terminal region of Aβ, especially the G33-L34-M35 segment, plays a particular role in the early steps of temperature-induced Aβ aggregation. In Aβ42, the distinct dynamical behaviour of C-terminal residues at higher temperatures is accompanied with marked changes in the backbone dynamics of residues V24-K28. The distinctive role of the C-terminal region of Aβ42 in the initiation of aggregation defines a target for the rational design of Aβ42 aggregation inhibitors.

Keywords: Alzheimer's disease; NMR spectroscopy; aggregation; amyloid beta-peptides; singlet-state.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Humans
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation
  • Protein Folding


  • Amyloid beta-Peptides