The generation and characterization of potentially therapeutic Abeta antibodies in mice: differences according to strain and immunization protocol.

Previous studies have shown that in various mouse models of Alzheimer's disease (AD), amyloid beta-protein (Abeta) antibodies generated by Abeta peptide immunization resulted in the prevention of Abeta plaque formation in brains of young mice, decreased Abeta plaque burdens in older mice and improved cognition. The purpose of this study was to optimize Abeta immunization protocols for future trials in transgenic mouse models of AD. The timing and titers of Abeta antibody production, as well as epitope(s) and imunoglobulin isotypes, were compared between two different mouse strains (C57BL/6 and B6D2F1) and five treatment protocols: (1). chronic Abeta nasal administration, (2). repeated Abeta intraperitoneal (i.p.) injection, (3). one i.p. injection followed by chronic Abeta nasal administration, (4). chronic and concurrent Abeta nasal administration + Abeta i.p. injection, and (5). untreated controls. B6D2F1 mice generated Abeta antibodies earlier and in higher quantities than the C57BL/6 mice, indicating that B6D2F1 mice are more responsive to Abeta immunization. For both strains, mice that received the combination of Abeta nasal + Abeta i.p. injection showed the highest antibody titers. Epitope mapping experiments indicated that the mouse anti-Abeta antibodies recognize residues within Abeta1-15. Immunoglobulin isotyping demonstrated that the Abeta antibodies are of the Th-2 anti-inflammatory type, IgG1 and IgG2b, with a few IgM. Currently there is no effective therapy for Alzheimer's disease; thus if Abeta immunization proves effective, it would be a significant step in the prevention and/or treatment of this devastating disease.