From the abstracts published for the upcoming Society for Neuroscience meeting in Chicago, starting on Sat., Oct. 7.
BJ
Title: Distinct amino-terminal conformations of A-beta revealed from comparative x-ray crystallographic studies of A-beta complexed with Fab fragments of antibodies recognizing different amino-terminal epitopes
Presentation Time: Sunday, Oct 18, 2009, 3:00 PM - 3:15 PM
Authors: *G. BASI1, H. FEINBERG2, F. OSHIDARI1, R. BARBOUR1, M. BUTTINI1, T. COMERY3, L. DIEP1, D. GILL4, K. JOHNSON-WOOD1, A. GOEL1, M. LEE1, D. WALKER1, A. WIDOM4, M. N. PENGALOS3, D. GAMES1, P. SEUBERT1, S. JACOBSEN3, W. I. WEIS2, D. SCHENK1;
1Elan Pharmaceuticals, South San Francisco, CA; 2Structural Biology, and Mol. and Cell. Physiol., Stanford Univ., Stanford, CA; 3Discovery Neurosci., Wyeth Res., Princeton, NJ; 4Biol. Technologies, Wyeth Res., Cambridge, MA
Abstract: Immunotherapy targeting A-beta peptide has been demonstrated to prevent or reverse a range of amyloid related pathologies in both transgenic mouse models and patients with Alzheimer’s disease (AD). In addition, an improvement in a number of behavioral deficits has been reported in mouse and primate models of AD following immunotherapy. Successes with immunotherapy in pre-clinical studies have provided impetus for testing anti-amyloid targeted immunotherapy for treatment of AD in humans, and multiple approaches are currently being tested in clinical trials. A number of important scientific questions remain however, regarding A-beta immunotherapy. These include: which epitope to target, which form of A-beta to target (e.g. soluble oligomeric vs. plaque associated), and elucidation of the mechanisms of action (e.g. plaque clearance via peripheral vs. central pathway). To gain further insight into these issues, we investigated the distinctions among antigen conformation recognized by different antibodies targeting amino-terminal epitopes of A-beta using x-ray crystallography of antibody:A-beta co-complexes. The antibodies in our study recognize soluble and toxic forms of A-beta, as well as plaque associated A-beta. The antibodies are also efficacious for acute reversal of behavioral deficits, and chronic reversal of plaque associated pathologies in transgenic mouse models of Alzheimer’s disease. We determined x-ray structures of antibody:A-beta complexes which revealed that three independently derived antibodies targeting A-beta residues 3-7 recognize antigen in an extended conformation along the surface of the antibody binding site. In contrast, an antibody targeting A-beta residues 1-5 recognizes antigen in a 310 helical conformation, with the amino-terminus of the peptide buried in the antibody binding site, and the C-terminus winding out to the surface of the antibody. Our observations reveal two discrete conformations adopted by amino-terminal epitope of A-beta in its multiple native states, and provide a possible basis for understanding in-vivo activities of antibodies targeting amino-terminal epitopes of A-beta. |
