Amyloid-β–anti-amyloid-β complex structure reveals an extended in the immunodominant conformation B-Cell epitope
Date
2008
Authors
Miles, L.
Wun, K.
Crespi, G.
Fodero-Tavoletti, M.
Galatis, D.
Bagley, C.
Beyreuther, K.
Masters, C.
Cappai, R.
McKinstry, W.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Molecular Biology, 2008; 377(1):181-192
Statement of Responsibility
Luke A. Miles, Kwok S. Wun, Gabriela A. N. Crespi, Michelle T. Fodero-Tavoletti, Denise Galatis, Christopher J. Bagley, Konrad Beyreuther, Colin L. Masters, Roberto Cappai, William J. McKinstry, Kevin J. Barnham and Michael W. Parker
Conference Name
Abstract
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.