Molecular basis for passive immunotherapy of Alzheimer's disease

Amyloid aggregates of the amyloid-beta (A beta) peptide are implicated in the pathology of Alzheimer's disease. Anti-A beta monoclonal antibodies (mAbs) have been shown to reduce amyloid plaques in vitro and in animal studies. Consequently, passive immunization is being considered for treating Alzheimer's, and anti-A beta mAbs are now in phase II trials. We report the isolation of two mAbs (PFA1 and PFA2) that recognize A beta monomers, protofibrils, and fibrils and the structures of their antigen binding fragments (Fabs) in complex with the A beta(1-8) peptide DAEFRHDS. The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and hydrophobic contacts, including interactions with a striking WWDDD motif of the antigen binding fragments. We also show that a similar sequence (AKFRHD) derived from the human protein GRIN is able to cross-react with both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an identical conformation to A beta(1-8). Because such cross-reactivity has implications for potential side effects of immunotherapy, our structures provide a template for designing derivative mAbs that target A beta with improved specificity and higher affinity.