Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell...

Alzheimer's disease (AD) is the most common form of dementia. Amyloid-beta (A beta) peptide, generated by proteolytic cleavage of the amyloid precursor protein, is central to AD pathogenesis. Most pharmaceutical activity in AD research has focused on A beta, its generation and clearance from the brain. In particular, there is much interest in immunotherapy approaches with a number of anti-A beta antibodies in clinical trials. We have developed a monoclonal antibody, called WO2, which recognises the A beta peptide. To this end, we have determined the three-dimensional structure, to near atomic resolution, of both the antibody and the complex with its antigen, the A beta peptide. The structures reveal the molecular basis for WO2 recognition and binding of A beta. The A beta peptide adopts an extended, coil-like conformation across its major immunodominant B-cell epitope between residues 2 and 8. We have also studied the antibody-bound A beta peptide in the presence of metals known to affect its aggregation state and show that WO2 inhibits these interactions. Thus, antibodies that target the N-terminal region of A beta, such as WO2, hold promise for therapeutic development.