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Articles, Neurobiology of Disease

The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice

Bin Zhang, Jenna Carroll, John Q. Trojanowski, Yuemang Yao, Michiyo Iba, Justin S. Potuzak, Anne-Marie L. Hogan, Sharon X. Xie, Carlo Ballatore, Amos B. Smith III, Virginia M.-Y. Lee and Kurt R. Brunden
Journal of Neuroscience 14 March 2012, 32 (11) 3601-3611; DOI: https://doi.org/10.1523/JNEUROSCI.4922-11.2012
Bin Zhang
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Jenna Carroll
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John Q. Trojanowski
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Yuemang Yao
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Michiyo Iba
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Justin S. Potuzak
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Anne-Marie L. Hogan
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Sharon X. Xie
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Carlo Ballatore
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Amos B. Smith III
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Virginia M.-Y. Lee
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Kurt R. Brunden
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    Figure 1.

    Comparison of axonal dystrophy in vehicle- or EpoD-treated 12-month-old PS19 and WT mice. The number of dystrophic axons per unit area of ON was determined for WT or PS19 mice that had received administration of either vehicle or EpoD from 9 to 12 months of age. A, A representative micrograph showing examples of dystrophic axons (arrows). Scale bar, 0.5 μm. B, Quantification of the number of dystrophic axons per area for the various treatment groups. Error bars indicate SEM; *p < 0.05, **p < 0.01, as determined by one-way ANOVA and Tukey's multiple-comparison test, with n = 8–10 mice evaluated/group. Veh, Vehicle.

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    Figure 2.

    Assessment of ON MT density in vehicle- or EpoD-treated 12-month-old mice PS19 and WT mice. A, Cross sections of the ON were imaged at 50,000× (scale bar, 500 nm), and hexagonal fields of 0.035 μm2 were arrayed over the ON images. B, An expanded image, with MTs identified by arrows in one hexagon. To avoid repeat counting of MTs that reside on a hexagon border, only those MTs that were on three of the six borders of each hexagon, as indicated, were included in the counts. C, ON MT density in WT or PS19 mice treated with vehicle or EpoD at the indicated dose. Error bars indicate SEM; *p < 0.05, as determined by one-way ANOVA and Tukey's multiple-comparison test, with n = 8–10 mice/group. Veh, Vehicle.

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    Figure 3.

    Comparison of ON FAT in vehicle- or EpoD-treated 12-month-old mice PS19 and WT mice. The extent of proximal-to-distal FAT along the ONs of WT or PS19 mice that had been dosed with vehicle or EpoD from 9 to 12 months of age as judged by [35S]methionine labeling of newly synthesized ON proteins and evaluation of the proximal-to-distal distribution of a transported protein as quantified by densitometric analysis of autoradiographs. A, SDS-PAGE autoradiographs of 35S-labeled proteins from ON segments of vehicle- and EpoD-treated PS19 mice. Each gel contains ON segments from a single mouse, with the lanes corresponding to individual 1 mm ON segments. The arrows in each gel depict the band that was quantified, with the migration of molecular markers indicated. B, Mean values for the proximal-to-distal distribution of the selected protein band. Error bars indicate SEM; *p < 0.05, ***p < 0.001, as determined using a mixed effect statistical model as described in Materials and Methods, with n = 3 mice evaluated/group.

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    Figure 4.

    Cognitive evaluation of vehicle- or EpoD-treated 12-month-old PS19 and WT mice. A–C, Y-maze testing of spontaneous alternation (SA) behavior (A), and Barnes maze performance as judged by the percentage of trials that were successfully completed (B) and the time taken to identify the correct target (C) with WT or PS19 mice that had received vehicle or EpoD from 9 to 12 months of age. Error bars indicate SEM; *p < 0.05, **p < 0.01, ***p < 0.001, as determined for (A) by one-way ANOVA and Tukey's multiple-comparison test, and for (B, C) by a repeated measures statistical analysis, with n = 10–12 mice/group. veh, Vehicle.

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    Figure 5.

    Assessment of tau pathology in the brains of vehicle- or EpoD-treated 12-month-old mice PS19. A, Low-power and higher power images of AT8 phospho-tau immunostaining, with the regions sampled for the 20× images denoted by boxes. The immunohistochemical (IHC) scores assigned to the vehicle- and EpoD-treated PS19 mice in these examples were 4 and 2, respectively. B, Low-power and higher power images of MC1 misfolded-tau immunostaining, with the regions sampled for the higher power images denoted by boxes. The IHC scores assigned to the vehicle- and EpoD-treated PS19 mice in these examples were 4 and 2, respectively. Scale bars, 1 mm in the low-power images, and 0.1 mm in the higher power images. C, D, Quantification of the extent of phospho-tau (C) and misfolded tau (D) in the forebrains of PS19 mice that had received vehicle or EpoD from 9 to 12 months of age, as determined by a semiquantitative rating of immunohistochemical staining using AT8 or MC1 monoclonal antibodies, respectively. E, The amount of insoluble tau in hemi-brain homogenates from vehicle- or EpoD-treated 12-month-old PS19 mice as determined with a tau ELISA. Error bars indicate SEM; *p < 0.05 as determined by a nonparametric Kruskal–Wallis analysis and Dunn's multiple-comparison test (C, D), or ANOVA and Tukey's multiple-comparison test (E); n = 9–10 mice/group.

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    Figure 6.

    A, B, Comparison of MC1 (A) and AT8 (B) immunohistochemical (IHC) scores with relative insoluble tau amount as determined by ELISA analysis of brain homogenates for each vehicle- and EpoD-treated PS19 mouse. The line represents the best linear fit of the data; r = correlation coefficient.

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    Figure 7.

    Assessment of hippocampal CA3 neurons in the brains of vehicle- or EpoD-treated 12-month-old mice PS19. A, B, Low-power representative images of hippocampal NeuN immunostaining from 12-month-old vehicle-treated WT (A) and PS19 (B) mice, with the regions sampled for quantification of 20× images denoted by boxes. C, Quantification of the CA3 NeuN area in WT or PS19 mice treated with vehicle or EpoD at the indicated dose. All data are normalized to the mean area obtained in the vehicle-treated WT mice. Error bars indicate SEM; *p < 0.05, as determined by one-way ANOVA and Tukey's multiple-comparison test, with n = 8–10 mice/group. Veh, Vehicle.

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    Figure 8.

    Evaluation of hippocampal synaptic and axonal density in the brains of vehicle- or EpoD-treated 12-month-old mice PS19. A, B, Representative images (20×) of hippocampal CA3 synaptophysin immunostaining from 12-month-old vehicle-treated WT (A) and PS19 (B) mice, with the demarcated area quantified. C, Quantification of the CA3 synaptophysin-positive area in WT or PS19 mice treated with vehicle or EpoD at the indicated dose. D, E, Representative images (20×) of hippocampal NFL immunostaining from 12-month-old vehicle-treated WT (D) and PS19 (E) mice, with the demarcated area quantified. F, Quantification of the CA3 NFL-positive area in WT or PS19 mice treated with vehicle or EpoD at the indicated dose. All data are normalized to the mean area obtained in the vehicle-treated WT mice. Error bars indicate SEM; *p < 0.05, as determined by one-way ANOVA and Tukey's multiple-comparison test, with n = 8–10 mice/group.

  • Figure 9.
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    Figure 9.

    Toxicological evaluation of vehicle- and EpoD-treated 12-month-old PS19 mice. A–D, WT or PS19 mice that had received vehicle or EpoD from 9 to 12 months of age were evaluated for final body weights (A), organ weights (B), WBC counts and percentage of WBCs that are neutrophils (C), and sensory nerve function using the von Frey test of footpad sensitivity (D). There were no statistically significant changes among any of the groups within these measures as determined by one-way ANOVA, with n = 8–10 mice/group. Veh/veh, Vehicle.

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The Journal of Neuroscience: 32 (11)
Journal of Neuroscience
Vol. 32, Issue 11
14 Mar 2012
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The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice
Bin Zhang, Jenna Carroll, John Q. Trojanowski, Yuemang Yao, Michiyo Iba, Justin S. Potuzak, Anne-Marie L. Hogan, Sharon X. Xie, Carlo Ballatore, Amos B. Smith III, Virginia M.-Y. Lee, Kurt R. Brunden
Journal of Neuroscience 14 March 2012, 32 (11) 3601-3611; DOI: 10.1523/JNEUROSCI.4922-11.2012

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The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice
Bin Zhang, Jenna Carroll, John Q. Trojanowski, Yuemang Yao, Michiyo Iba, Justin S. Potuzak, Anne-Marie L. Hogan, Sharon X. Xie, Carlo Ballatore, Amos B. Smith III, Virginia M.-Y. Lee, Kurt R. Brunden
Journal of Neuroscience 14 March 2012, 32 (11) 3601-3611; DOI: 10.1523/JNEUROSCI.4922-11.2012
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