Single-Chain Variable Fragment Antibodies Targeting Amyloid β Oligomers: Alzheimer’s Disease Toxins

Amyloid beta oligomers (AβOs) accumulate early in Alzheimer’s disease and experimentally cause memory dysfunction and the major cellular pathologies associated with AD (e.g., tau abnormalities, synapse loss, oxidative damage, etc.). However, the structures of the AβO species most germane to AD pathogenesis are ill-defined. This uncertainty regarding the pathophysiologically relevant AβO structures has diminished the perceived therapeutic value of targeting Aβ-derived toxins. Our long-term research goals are to identify AβO species germane to AD onset and to determine the structural characteristics of these AβOs that contribute to their role in the pathogenesis of AD. To help achieve this goal, we have identified multiple single-chain variable fragment (scFv) antibodies with high specificity for AβOs (and minimal affinity for Aβ monomers and fibrils) by panning phage-displayed human scFv libraries. We have determined that at least one of these scFvs, NUsc1, is specific for a small sub-population of synapse-binding AβOs. Furthermore, we have demonstrated that NUsc1 retains its AβO binding activity when it is expressed in soluble form, not attached to phage. The specificity of NUsc1, and the other AβO-specific scFvs, makes them promising tools for (1) determining the role of individual AβO conformations in AD pathogenesis; and (2) application as brain imaging probes for AD diagnostics (e.g., Viola et al., 2015, Nature Nanotechnology).