Learning Decreases Aβ*56 and Tau Pathology and Ameliorates Behavioral Decline in 3xTg-AD Mice

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Abstract
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 β (Aβ) 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 Aβ redistribution to extracellular plaques and reduces Aβ oligomers associated with cognitive decline. In addition, learning leads to decreased glycogen synthase kinase-3β 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.