Structural and functional analyses of pyroglutamate-amyloid-beta-specific antibodies as a basis for Alzheimer immunotherapy

Alzheimer disease is associated with deposition of the amyloidogenic peptide A in the brain. Passive immunization using A-specific antibodies has been demonstrated to reduce amyloid deposition both in vitro and in vivo. Because N-terminally truncated pyroglutamate (pE)-modified A species (A(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 A(pE3) with affinities of 1-10 nm and inhibit A(pE3) fibril formation in vitro. In vivo application of one of these resulted in improved memory in A(pE3) oligomer-treated mice. Crystal structures of F-ab-A(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 A(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.