Structural and functional analyses of pyroglutamate-amyloid-β-specific antibodies as a basis for Alzheimer...

Alzheimer disease is associated with deposition of the amyloidogenic peptide Aβ in the brain. Passive immunization using Aβ-specific antibodies has been demonstrated to reduce amyloid deposition both in vitro and in vivo Because N-terminally truncated pyroglutamate (pE)-modified Aβ species (Aβ_pE3) exhibit enhanced aggregation potential and propensity to form toxic oligomers, they represent particularly attractive targets for antibody therapy. Here we present three separate monoclonal antibodies that specifically recognize Aβ_pE3 with affinities of 1-10 nm and inhibit Aβ_pE3 fibril formation in vitro. In vivo application of one of these resulted in improved memory in Aβ_pE3 oligomer-treated mice. Crystal structures of F_ab-Aβ_pE3 complexes revealed two distinct binding modes for the peptide. Juxtaposition of pyroglutamate pE3 and the F4 side chain (the "pEF head") confers a pronounced bulky hydrophobic nature to the Aβ_pE3 N terminus that might explain the enhanced aggregation properties of the modified peptide. The deep burial of the pEF head by two of the antibodies explains their high target specificity and low cross-reactivity, making them promising candidates for the development of clinical antibodies.