Single-domain antibodies recognize selectively small oligomeric forms of amyloid β, prevent Aβ-induced neurotoxicity and inhibit fibril formation

Neurotoxic oligomers of amyloid β (Aβ) peptide have been incriminated in the pathogenesis of Alzheimer’s disease. Further exploration of this issue has been hampered to this date by the fact that all previously described anti-Aβ antibodies are unable to discriminate between the different conformations of the peptide (oligomers, protofibrils and fibrils). Here, we describe the generation of novel camelid single-chain binding domains (VHHs) that recognizes specifically low molecular-weight (MW) oligomers. Three VHH specific for Aβ were obtained from an immunized alpaca phage display library. Two were able to recognize selectively intraneuronal Aβ oligomers; furthermore, one of them, V31-1, prevented Aβ-induced neurotoxicity and inhibited fibril formation. This study confirms that VHHs may recognize non-conventional epitopes and illustrates their potential for the immunodiagnostic of diseases due to protein accumulation.