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Articles, Neurobiology of Disease

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

Lauren M. Billings, Kim N. Green, James L. McGaugh and Frank M. LaFerla
Journal of Neuroscience 24 January 2007, 27 (4) 751-761; DOI: https://doi.org/10.1523/JNEUROSCI.4800-06.2007
Lauren M. Billings
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Kim N. Green
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James L. McGaugh
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Frank M. LaFerla
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    Figure 1.

    Study design. Separate groups of mice were trained and tested on the Morris water maze. In study 1, mice were trained either longitudinally or cross-sectionally. In study 2, a separate group of mice was trained longitudinally to 12 months of age, after which they were killed, and their brains were examined and compared with brains of mice trained only at 12 months of age for alterations in neuropathology. In study 3, mice were trained after the emergence of overt neuropathology (delayed training) to examine the ability of longitudinal training to affect established pathology. In addition, a group of yoked mice were subjected to similar handling, motor assessment, and swimming as the mice in studies 1 and 2 but were not trained to find a platform in the MWM. These mice were then trained on the MWM at 12 months of age to determine the contribution of previous learning, rather than exposure to the activity per se, on subsequent learning and memory in the MWM. For the number of animals in each study, see Table 1.

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    Figure 2.

    Longitudinal training improves MWM acquisition in the 3xTg-AD mice. Although all groups of experienced mice exhibited improved acquisition after repeated MWM training (A–D), this training effect was especially pronounced in 3xTg-AD mice. In particular, at 12 months of age, 3xTg-AD-h and 3xTg-AD-H mice were virtually indistinguishable from NonTg mice (A,C,D), whereas naive 3xTg-AD mice were severely impaired at every age after 6 months (C,D). However, at 15 months of age, 3xTg-AD mice were markedly impaired in MWM acquisition regardless of whether they had been previously trained or not. Specifically, at 15 months of age, homozygous 3xTg-AD mice showed significant acquisition deficits (D). However, a genotype effect was still present with hemizygous 3xTg-AD mice continuing to exhibit a training effect at 15 months of age (C). Each cluster of results represents the daily means across each group. Error bars indicate SE.

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    Figure 3.

    Previous experience on MWM induces a marked, albeit transient, improvement in acquisition. Naive 3xTg-AD mice (A) are markedly impaired during acquisition relative to NonTg mice, whereas experienced 3xTg-AD mice (B) exhibit a clear benefit of previous training that emerges at 9 months of age and gradually disappears by 15–18 months of age. Each cluster of results represents the daily means across each group. Error bars indicate SE.

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    Figure 4.

    Previous training improves memory retention. At 9 months of age, experienced 3xTg-AD-H mice exhibit improved retention for the platform location at both 1.5 and 24 h after training (A). However, a more marked effect of training appeared at 12 months of age at which the 3xTg-AD mice exhibit no deficit at 1.5 h and are only impaired at 24 h (B), similar to 4-month-old 3xTg mice. By 15 months, however, previous training does not benefit memory because both experienced and naive 3xTg-AD mice are significantly impaired in both MWM probe trials (C). *p < 0.05 with respect to NonTg mice;ϕp < 0.05 with respect to the corresponding experienced group.

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    Figure 5.

    Experience decreases extracellular Aβ plaque formation. Aβ pathology was investigated in the 12 month experienced (denoted as E) 3xTg-AD mice and naive (denoted as N) 3xTg-AD-H mice to determine whether changes in pathology underlie cognitive improvements. 6E10 immunofluorescence illustrated increased Aβ plaque load and associated activated microglia (CD45) in the naive compared with the experienced mice (A). Quantification of plaque numbers revealed a significant decrease in the experienced animals (B). Correspondingly, sandwich ELISA Aβ40 and Aβ42 measurements showed increased soluble Aβ (C) but decreased insoluble Aβ in the experienced group (D). Steady-state levels of APP and the APP fragments C83 and C99 were unchanged (E) between groups as quantified and normalized to β-actin levels (F). Marked reductions in the Aβ degrading enzymes neprilysin and IDE were seen in the experienced animals (G) as quantified and normalized to β-actin levels (H), suggesting that Aβ plaque load did not stimulate increased Aβ degradation. *p < 0.05 significant differences with respect to naive mice.

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    Figure 6.

    Experience diminishes Aβ oligomers formation and phospho-tau through GSK-3β. Additional characterization of Aβ pathology in the experienced (denoted as E) 12 month 3xTg-AD mice against the naive (denoted as N) animals revealed a decrease in Aβ oligomers levels, as shown by A11 dot blot (A, quantified inE;p = 0.051). Analysis of 6E10 blots revealed differences in a band picked up at 56 kDa, which has been linked previously to cognitive decline, which significantly decreased in the experienced animals (B). In support of this band being, at least in part, made up of Aβ oligomers (12-mers), 10% HFIP treatment, which is known to break up oligomers, was found to decrease this band (C). To explore further why Aβ pathology was not relocalized in the experienced animals, as in the naive, putative Aβ transporter steady-state levels were investigated (D), and significant reduction was seen in LRP light chain but no differences in ApoE or TGF1β, as quantified and normalized to β-actin levels (E). Given the apparent retardation of Aβ pathology in the experienced group and the sequential relationship between Aβ and tau pathology, phosphorylated tau steady-state levels were studied. Whereas steady-state levels of total tau were unaltered, phosphorylation at AT8, AT180, and AT270 sites were significantly reduced in the experienced animals (F) as quantified and normalized to β-actin (G). Steady-state levels of GSK3β or Cdk5 were unaffected, as were levels of p25 and p35, which can underlie tau phosphorylation (H). However, phosphorylated GSK3β at Ser9, an inhibitory phosphorylation site, was significantly increased in the experienced group, indicating decreased GSK3β activity as quantified and normalized to β-actin (I). *p < 0.05 with respect to naive mice.

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    Figure 7.

    Training before the development of overt neuropathology is required for full benefit of longitudinal training. In the initial longitudinal study (seeFig. 1) (experienced mice, denoted as E), mice were trained and tested before the development of overt neuropathology. To assess the importance of training before the emergence of overt Aβ and tau neuropathology, a separate group of mice were trained and tested at 6, 9, and 12 months after they had developed early Aβ and tau deposits (delayed training mice, denoted as DT). In addition, a separate group of mice were made to swim the daily mean only at 2, 6, and 9 months but were trained and tested as all other groups at 12 months of age. This yoked (denoted as Y) group was included to control for exposure to the handling and the learning environment in the absence of a learning contingency. Although the 3xTg-AD DT mice learned similarly to experienced mice (B,C), homozygous 3xTg-AD mice trained after the emergence of overt neuropathology were significantly impaired during probe trials relative to experienced mice at 9 and 12 months of age (F). Yoked mice were substantially impaired during acquisition, across all genotypes (A–C), perhaps attributable to a learned helplessness in response to the water maze. However, the NonTg yoked mice eventually acquired the task and exhibited no impairment during probe trials (D). In contrast, although the yoked 3xTg-AD mice eventually reached MWM criterion during training (B,C), they were significantly impaired during probe trials (E, F). *p < 0.05 with respect to NonTg mice;ϕp < 0.05 with respect to the corresponding experienced group.

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The Journal of Neuroscience: 27 (4)
Journal of Neuroscience
Vol. 27, Issue 4
24 Jan 2007
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Learning Decreases Aβ*56 and Tau Pathology and Ameliorates Behavioral Decline in 3xTg-AD Mice
Lauren M. Billings, Kim N. Green, James L. McGaugh, Frank M. LaFerla
Journal of Neuroscience 24 January 2007, 27 (4) 751-761; DOI: 10.1523/JNEUROSCI.4800-06.2007

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Learning Decreases Aβ*56 and Tau Pathology and Ameliorates Behavioral Decline in 3xTg-AD Mice
Lauren M. Billings, Kim N. Green, James L. McGaugh, Frank M. LaFerla
Journal of Neuroscience 24 January 2007, 27 (4) 751-761; DOI: 10.1523/JNEUROSCI.4800-06.2007
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