A genetically encoded selection for amyloid-β oligomer binders

Soluble amyloid beta oligomers (AβOs) are a hypothesized source of neurotoxicity in Alzheimer’s Disease. Binding proteins that recognize these species may have high utility in diagnostic and therapeutic applications. However, identifying binders that recognize AβOs directly generated from the aggregation cascade is made challenging by the short lifetime and low concentrations of oligomer populations. We report a new strategy for detecting binding to AβOs as they form during Aβ42 aggregation using a genetically encoded biosensor. We show that our method enables rapid and highly reproducible measurement of the activity of existing AβO binders and can be used to select for new binders with improved potency. We uncover hits that are >20 fold more effective than reported binders at delaying secondary nucleation, the step in Aβ aggregation thought to generate the highest amounts of toxic oligomers. Our approach may greatly accelerate the discovery and characterization of binding proteins that target AβOs.