Trapping and Characterization of Nontoxic Aß42 Aggregation Intermediates.

Amyloid ß (Aß) 42 is an aggregation-prone peptide and the believed seminal etiological agent of Alzheimer's disease (AD). Intermediates of Aß42 aggregation, commonly referred to as diffusible oligomers, are considered to be among the most toxic forms of the peptide. Here, we studied the effect of the age-related epimerization of Ser26 (i.e., S26s chiral edit) in Aß42 and discovered that this subtle molecular change led to reduced fibril formation propensity. Surprisingly, the resultant soluble aggregates were nontoxic. To gain insight into the structural changes that occurred in the peptide upon S26s substitution, the system was probed using an array of biophysical and biochemical methods. These experiments consistently pointed to the stabilization of aggregation intermediates in the Aß42-S26s system. To better understand the changes arising as a consequence of the S26s substitution, molecular level structural studies were performed. Using a combined nuclear magnetic resonance (NMR)- and density functional theory (DFT)-computational approach, we found that the S26s chiral edit induced only local structural changes in the Gly25-Ser26-Asn27 region. Interestingly, these subtle changes enabled the formation of an intramolecular Ser26-Asn27 H-bond, which disrupted the ability of Asn27 to engage in the fibrillogenic side chain-to-side chain H-bonding pattern. This reveals that intermolecular stabilizing interactions between Asn27 side chains are a key element controlling Aß42 aggregation and toxicity.