Development of β-sheet structure in Aβ 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 β  peptide (Aβ) in Alzheimer's disease (AD). Understanding the distinct properties between Aβ 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 Aβ species comprising lower molecular weight  oligomers  up to larger protofibrils. In the current study, a number of strategies were utilized to separate Aβ protofibrils and oligomers and show that the smaller Aβ oligomers have a much different conformation than Aβ protofibrils. The differences were consistent for both Aβ40 and Aβ42. Protofibrils bound  thioflavin  T to a greater extent than oligomers, and were highly enriched in β-sheet  secondary structure . Aβ 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 Aβ protofibrils ultimately proved critical for provoking the release of tumor necrosis factor  α  from microglial cells. The findings demonstrated a dependency on β-sheet structure for soluble Aβ aggregates to cause a microglial inflammatory response. The Aβ aggregation process yields many conformationally-varied species with different levels of β-structure and exposed  hydrophobicity . The conformation elements likely determine biological activity and pathogenicity.