Early Divergence in Misfolding Pathways of Amyloid-Beta Peptides.

Abstract

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.