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The Journal of Neuroscience, March 7, 2007, 27(10):2654-2662; doi:10.1523/JNEUROSCI.3710-06.2007
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Neurobiology of Disease
Active ß-Amyloid Immunization Restores Spatial Learning in PDAPP Mice Displaying Very Low Levels of ß-Amyloid
Guiquan Chen,1 Karen S. Chen,2 Dione Kobayashi,2 Robin Barbour,2 Ruth Motter,2 Dora Games,2 Stephen J. Martin,1 andRichard G. M. Morris1 1Laboratory for Cognitive Neuroscience, Centre for Cognitive and Neural Systems, Edinburgh EH8 9JZ, United Kingdom, and 2Elan Pharmaceuticals, South San Francisco, California 94080
Correspondence should be addressed to Richard G. M. Morris, Centre and Division of Neuroscience, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK. Email: r.g.m.morris{at}ed.ac.uk
The behavioral and biochemical impact of active immunization against human ß-amyloid (Aß) was assessed using male transgenic (Tg) mice overexpressing a human mutant amyloid precursor protein (heterozygous PDAPP mice) and littermate controls. Administration of aggregated Aß42 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 Aß42 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 Aß and Aß42 levels in cortex and hippocampus by up to 60%. In immunized PDAPP mice, significant negative correlations were observed between hippocampal and cortical Aß 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 Aß levels (hippocampal Aß levels of <6000 ng/g or cortical Aß 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 Aß 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.
Key words: Alzheimer's disease; animal models; vaccine; transgenic mouse; water maze; spatial learning
Received Aug. 25, 2006; revised Dec. 22, 2006; accepted Dec. 27, 2006.
Correspondence should be addressed to Richard G. M. Morris, Centre and Division of Neuroscience, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK. Email: r.g.m.morris{at}ed.ac.uk
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