Novel
amyloid precursor
protein transgenic mice, which contain the Swedish as well as the vasculotropic Dutch and Iowa mutations (Tg-SwDI), were used to investigate the mechanisms of antibody-mediated clearance of
amyloid-beta (Abeta) from the brain. Export of the Abeta-DI
peptide across the blood-brain barrier is severely reduced because of the vasculotropic mutations. Therefore, antibody-mediated clearance of Abeta-DI is dependent on
antibodies entering the brain. In this report, we immunized Tg-SwDI mice with various
peptide antigens, including Abeta40-DI, Abeta42, and an Abeta
epitope vaccine. Immunization of Tg-SwDI mice with substantial cortical diffuse and vascular fibrillar deposits failed to promote clearance of parenchymal or vascular
amyloid deposits. We then immunized young Tg-SwDI mice before the accumulation of Abeta and saw no evidence that anti-Abeta
antibodies could diminish deposition of parenchymal or vascular
amyloid deposits. However, injection of anti-Abeta
antibodies, affinity-purified from immunized Tg-SwDI mice, into the hippocampus induced a rapid clearance of diffuse Abeta deposits but not vascular
amyloid deposits. These results further support the "peripheral sink hypothesis" as a legitimate mechanism of antibody-mediated clearance of Abeta when the blood-brain barrier remains intact. Thus, approaches that deliver
immunotherapy to the brain may be more effective at clearing Abeta than immunization strategies in which the majority of the
antibodies are in the periphery.