. Molecular basis for passive immunotherapy of Alzheimer's disease. Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15659-64. PubMed.


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  1. Anti-amyloid immunotherapy remains one of the front-line strategies for the development of Alzheimer therapeutics. Both passive and active immunization are currently under active development for human clinical application. Antibodies that target the amino terminus of Aβ seem particularly interesting. Not only does this region appear to be an immuno-dominant site, but antibodies that recognize epitopes in this region also seem particularly effective in reversing AD pathogenesis in transgenic animals and in depolymerizing amyloid fibrils in vitro. In this article, Chris Dealwis and colleagues report the crystal structures of two monoclonal antibodies that target the amino terminus of Aβ.

    These antibodies, PFA1 and PFA2, are remarkably specific for the EFRHD sequence at residues 3-7 of the Aβ peptide, as substitution of an alanine residue at any position nearly eliminates antibody binding. The crystal structures of the Fab complex with the peptide DAEFRHDS reveals that a WWDDD motif in the heavy chain complementarity determining region (CDR) of the antibodies forms salt bridges, hydrogen bonds, and hydrophobic contacts with the EFRHD sequence of Aβ.

    Although both PFA1 and PFA2 are remarkably specific for the EFRHD sequence, the authors show that a similar sequence (AKFRHD) derived from the human protein GRIP1 also reacts with the monoclonal antibodies. This raises the possibility of undesirable cross-reactivity with other human proteins; however, the structure of the antigen combining site suggests that one could redesign the CDRs to eliminate undesired cross-reactivity.

    The amino terminus of Aβ is also interesting because it seems to contain a conformational switch associated with aggregation and is the site that some conformation-dependent antibodies recognize. The fact that antibodies directed against this region depolymerize amyloid fibrils suggests that antibody binding induces a structure that is incompatible with the amyloid fibril lattice (1). The amino terminus is also the site of a conformation-dependent epitope recognized by the M16 polyclonal antisera that is specific for Aβ aggregates and fibrils, but does not recognize Aβ monomer or APP (2).


    . High affinity binding of monoclonal antibodies to the sequential epitope EFRH of beta-amyloid peptide is essential for modulation of fibrillar aggregation. J Neuroimmunol. 1999 Mar 1;95(1-2):136-42. PubMed.

    . The influence of the carboxyl terminus of the Alzheimer Abeta peptide on its conformation, aggregation, and neurotoxic properties. Neuromolecular Med. 2002;1(1):81-94. PubMed.