Active β-amyloid immunization restores spatial learning in PDAPP mice displaying very low levels of β-amyloid

The behavioral and biochemical impact of active immunization against human beta-amyloid (A beta) was assessed using male transgenic (Tg) mice overexpressing a human mutant amyloid precursor protein (heterozygous PDAPP mice) and littermate controls. Administration of aggregated A beta(42) occurred at monthly intervals from 7 months ("prevention") or 11 months ("reversal"), followed by double-blind behavioral training at 16 months on a cued task, then serial spatial learning in a water maze. Using a 2 x 2 design, with A beta(42) adjuvanted with MPL-AF (adjuvant formulation of monophosphoryl lipid A) or MPL-AF alone, PDAPP mice were impaired compared with non-Tg littermates on two separate measures of serial spatial learning. Immunization caused no overall rescue of learning but limited the accumulation of total A beta and A beta(42) levels in cortex and hippocampus by up to 60%. In immunized PDAPP mice, significant negative correlations were observed between hippocampal and cortical A beta levels and learning capacity, particularly in the prevention study, and correlations between learning capacity and antibody titer. Moreover, a subset of PDAPP mice with very low A beta levels (hippocampal A beta levels of < 6000 ng/g or cortical A beta levels of < 1000 ng/g) was indistinguishable from non-Tg controls. Mice in the prevention study were also rescued from cognitive impairment more effectively than those in the reversal study. The combination of variability in antibody response and differential levels of A beta accumulation across the population of immunized PDAPP mice may be responsible for success in cognitive protection with only a subset of these animals, but the similarity to the findings of certain human vaccination trials is noteworthy.