Vaccination with soluble Aβ oligomers generates toxicity-neutralizing antibodies

Abstract

In recent studies of transgenic models of Alzheimer's disease (AD), it has been reported that antibodies to aged beta amyloid peptide 1-42 (Aβ1-42) solutions (mixtures of Aβ monomers, oligomers and amyloid fibrils) cause conspicuous reduction of amyloid plaques and neurological improvement. In some cases, however, neurological improvement has been independent of obvious plaque reduction, and it has been suggested that immunization might neutralize soluble, non-fibrillar forms of Aβ. It is now known that Aβ toxicity resides not only in fibrils, but also in soluble protofibrils and oligomers. The current study has investigated the immune response to low doses of Aβ1-42 oligomers and the characteristics of the antibodies they induce. Rabbits that were injected with Aβ1-42 solutions containing only monomers and oligomers produced antibodies that preferentially bound to assembled forms of Aβ in immunoblots and in physiological solutions. The antibodies have proven useful for assays that can detect inhibitors of oligomer formation, for immunofluorescence localization of cell-attached oligomers to receptor-like puncta, and for immunoblots that show the presence of SDS-stable oligomers in Alzheimer's brain tissue. The antibodies, moreover, were found to neutralize the toxicity of soluble oligomers in cell 'culture. Results support the hypothesis that immunizations of transgenic mice derive therapeutic benefit from the immunoneutralization of soluble Aβ-derived toxins. Analogous immuno-neutralization of oligomers in humans may be a key in AD vaccines.