A Hybrid Structural Method for Investigating Low Molecular Weight Oligomeric Structures of Amyloid Beta

Spurred in part by the failure of recent therapeutics targeting amyloid β plaques in Alzheimer's Disease (AD), attention is increasingly turning to the oligomeric forms of this peptide that form early in the aggregation process. However, while numerous amyloid β fibril structures have been characterized, primarily by NMR spectroscopy and cryo-EM, obtaining structural information on the low molecular weight forms of amyloid β that presumably precede and/or seed fibril formation has proved challenging. These transient forms are heterogeneous, and depend heavily on experimental conditions such as buffer, temperature, concentration, and degree of quiescence during measurement. Here, we present the concept for a new approach to delineating structural features of early-stage low molecular weight amyloid β oligomers, using a solvent accessibility assay in conjunction with simultaneous fluorescence measurements.