Experimental investigation of antibody-mediated clearance mechanisms of amyloid-β in CNS of Tg-SwDI transgenic mice

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(A beta) from the brain. Export of the A beta-DI peptide across the blood-brain barrier is severely reduced because of the vasculotropic mutations. Therefore, antibody-mediated clearance of A beta-DI is dependent on antibodies entering the brain. In this report, we immunized Tg-SwDI mice with various peptide antigens, including A beta(40)-DI, A beta(42), and an A beta 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 A beta and saw no evidence that anti-A beta antibodies could diminish deposition of parenchymal or vascular amyloid deposits. However, injection of anti-A beta antibodies, affinity-purified from immunized Tg-SwDI mice, into the hippocampus induced a rapid clearance of diffuse A beta deposits but not vascular amyloid deposits. These results further support the peripheral sink hypothesis as a legitimate mechanism of antibody-mediated clearance of A beta when the blood-brain barrier remains intact. Thus, approaches that deliver immunotherapy to the brain may be more effective at clearing A beta than immunization strategies in which the majority of the antibodies are in the periphery.