Development of ß-sheet structure in Aß aggregation intermediates diminishes exposed hydrophobic surface area and enhances proinflammatory activity

Three decades of research, both in vitro and in vivo, have demonstrated the conformational heterogeneity that is displayed by the amyloid ss peptide (A ss) in Alzheimer's disease (AD). Understanding the distinct properties between A ss conformations and how conformation may impact cellular activity remain open questions, yet still continue to provide new insights into protein misfolding and aggregation. In particular, there is interest in the group of soluble oligomeric prefibrillar A ss species comprising lower molecular weight oligomers up to larger protofibrils. In the current study, a number of strategies were utilized to separate A ss protofibrils and oligomers and show that the smaller A ss oligomers have a much different conformation than A ss protofibrils. The differences were consistent for both A ss 40 and A ss 42. Protofibrils bound thioflavin T to a greater extent than oligomers, and were highly enriched in ss-sheet secondary structure. A ss oligomers possessed a more open structure with significant solvent exposure of hydrophobic domains as determined by tryptophan fluorescence and bis-ANS binding, respectively. The protofibril-selective antibody AbSL readily discerned conformational differences between protofibrils and oligomers. The more developed structure for A ss protofibrils ultimately proved critical for provoking the release of tumor necrosis factor a from microglial cells. The findings demonstrated a dependency on ss-sheet structure for soluble A ss aggregates to cause a microglial inflammatory response. The A ss aggregation process yields many conformationally-varied species with different levels of ss-structure and exposed hydrophobicity. The conformation elements likely determine biological activity and pathogenicity.

Automated summary

Three decades of research have shown the conformational heterogeneity of amyloid β peptide (Aβ) in Alzheimer's disease (AD). The differences in conformation between Aβ species are still not fully understood, but they provide insights into protein misfolding and aggregation. In this study, different strategies were used to separate Aβ protofibrils and oligomers, and it was found that the smaller Aβ oligomers have a different conformation than Aβ protofibrils.