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The Journal of Neuroscience, January 24, 2007, 27(4):751-761; doi:10.1523/JNEUROSCI.4800-06.2007
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Neurobiology of Disease
Learning Decreases Aß*56 and Tau Pathology and Ameliorates Behavioral Decline in 3xTg-AD Mice
Lauren M. Billings,1,2 * Kim N. Green,1,2 * James L. McGaugh,1 andFrank M. LaFerla1,2 1Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory and 2Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California 92697-4545
Correspondence should be addressed to Frank M. LaFerla, Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, CA 92697-4545. Email: laferla{at}uci.edu
Transgenic mouse models of Alzheimer's disease (AD), such as the 3xTg-AD mice, are instrumental for elucidating genetic, pharmacologic, environmental, and behavioral factors that affect the cognitive phenotype. Here we present the novel findings that longitudinal water-maze spatial training produces a significant, albeit transient, improvement in subsequent learning performance and reduces amyloid ß (Aß) and tau neuropathology. The 3xTg-AD mice were trained and tested at 3 month intervals from 2 to 18 months. Separate groups of naive mice were also tested at each age. The improvement in performance seen at 6 and 12 months is dependent on spatial training, because animals that were similarly handled and exposed to swimming without a learning contingency failed to show improved performance. Training before the development of overt neuropathology is required for full expression of the training effect because we found it delays Aß redistribution to extracellular plaques and reduces Aß oligomers associated with cognitive decline. In addition, learning leads to decreased glycogen synthase kinase-3ß activity, which likely underlies the reduced tau pathology. The previous training effects on both maze performance and neuropathology are attenuated at 15 and 18 months. These findings indicate that, in young and middle-aged 3xTg-AD mice, repeated spatial training can significantly delay the development of neuropathology and decline in spatial memory.
Key words: tau; Alzheimer's disease; amyloid ß; behavior; cognition; transgenic
Received Aug. 11, 2006; revised Dec. 8, 2006; accepted Dec. 10, 2006.
Correspondence should be addressed to Frank M. LaFerla, Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, CA 92697-4545. Email: laferla{at}uci.edu
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