A Hairpin Motif in the Amyloid-β Peptide Is Important for Formation of Disease-Related Oligomers

Abstract

The amyloid-β (Aβ) peptide is associated with the development of Alzheimer's disease and is known to form highly neurotoxic prefibrillar oligomeric aggregates, which are difficult to study due to their transient, lowabundance, and heterogeneous nature. To obtain high-resolution information about oligomer structure and dynamics as well as relative populations of assembly states, we here employ a combination of native ion mobility mass spectrometry and molecular dynamics simulations. We find that the formation of Aβ oligomers is dependent on the presence of a specific β-hairpin motif in the peptide sequence. Oligomers initially grow spherically but start to form extended linear aggregates at oligomeric states larger than those of the tetramer. The population of the extended oligomers could be notably increased by introducing an intramolecular disulfide bond, which prearranges the peptide in the hairpin conformation, thereby promoting oligomeric structures but preventing conversion into mature fibrils. Conversely, truncating one of the β-strand-forming segments of Aβ decreased the hairpin propensity of the peptide and thus decreased the oligomer population, removed the formation of extended oligomers entirely, and decreased the aggregation propensity of the peptide. We thus propose that the observed extended oligomer state is related to the formation of an antiparallel sheet state, which then nucleates into the amyloid state. These studies provide increased mechanistic understanding of the earliest steps in Aβ aggregation and suggest that inhibition of Aβ folding into the hairpin conformation could be a viable strategy for reducing the amount of toxic oligomers.

Precision Proteoform Design for 4R Tau Isoform Selective Templated Aggregation

“…These studies suggest several entry points for 4R tauopathy interventions involving either nanobodies or small molecules, but all pointing to the structure of the R2R3 spanning hairpin and relative exposure of the PHF6 amyloidogenic sequence. Structural studies suggest a similar rationale might be applied to the amyloid-beta-peptide 66 . The observation suggests that aggregates are dynamically changing their size may offer a rationale for disaggregation approaches.…”

Perspective for Molecular Dynamics Simulation Studies of Amyloid-β Aggregates

“…The importance of β-hairpin structure for Aβ aggregation was shown by another group, too. Strodel, Österlund, and their collaborators employed native ion mobility mass spectrometry and MD simulations and found that the formation of Aβ oligomers depends on the presence of a specific β-hairpin motif . They also found that oligomers initially grow spherically but start to form linear aggregates at oligomeric states larger than those of the tetramer.…”

“…In the future, MD simulation will lead experiments studying Aβ and the other causative agents of various diseases. For example, now that the MD simulation studies have shown that β-hairpins promote aggregation, ,,, the author thinks that future research combining MD simulations and experiments may explore methods to inhibit the aggregation by designing antibodies that target the β-hairpin structure.…”

Microbiome-Derived Prion-Like Proteins and Their Potential to Trigger Cognitive Dysfunction

“…Remarkably, many Alzheimer's patients have experienced active and/or latent Helicobacter infections, suggesting a potential role for this pathogen in the development of the pathology 40,41 .…”