Fig 1.
rTg4510 mice exhibit increased LMA in an age-dependent manner.
(A) Averaged travel distance during a 30 min LMA test revealed increased LMA in 5-month-old rTg4510 mice compared to the WT littermates. (***p<0.001, t-test, n = 20 WT and 27 rTg4510 mice). (B) Time course distance traveled in 10-min bins. (* p<0.05, **p<0.01 compared to the first time bin, two-way ANOVA followed by Bonferroni post hoc test, n = 20 WT and 27 rTg4510 mice). (C) Five-month-old rTg4510 mice displayed similar percentage of center region activity as the WT littermates. (D) rTg4510 mice exhibited age-dependent increase in LMA. (***p<0.001 compared to 2-month-old rTg4510 mice, one-way ANOVA followed by Bonferroni post hoc test; n = 120, 124, 229, 190, and 36 per group for rTg4510 mice at 2, 3, 4, 5, 7 months of age, respectively).
Fig 2.
LMA in 5-month-old rTg4510 mice correlates with brain atrophy and NFT pathology.
(A), Negative correlation between LMA and forebrain weight (r = -0.52, p<0.01, n = 27). (B), Positive correlation between LMA and NFT pathology in entorhinal cortex (r = 0.58, p<0.01, n = 27). (C–D), Representative images of NFT pathology in entorhinal cortex of rTg4510 mice with LMA distance > 2000 cm (C) and < 2000 cm (D). Insets, higher magnification images of NFT bearing neurons in entorhinal cortex (Scale bar, 800 μm; 20 μm in inset).
Fig 3.
Correlation between LMA and brain hyperphosphorylated tau levels.
(A) LMA positively correlated with brain hyperphosphorylated tau detected by PHF6 alphaLISA in 5-month-old rTg4510 mice (r = 0.61, p < 0.001, n = 27). (B–C) Lack of correlation between LMA and brain hyperphosphorylated tau in rTg4510 mice at 2 months of age (B, r = 0.23, p = 0.25, n = 30) and 7 months of age (C, r = -0.09, p = 0.59, n = 36). (D) Plot of LMA distance as a function of brain hyperphosphorylated tau levels at 2, 5, and 7 months of age.
Fig 4.
Effects of doxycycline treatment on progression of hyperactivity in rTg4510 mice are age-dependent.
WT and rTg4510 mice were dosed with either normal mouse chow (Veh) or normal mouse chow containing doxycycline at 1g/kg (Dox) for 4 months starting at either 2 months of age (A) or 4 months of age (B). LMA was tested monthly after the onset of treatment to monitor the progression of hyperactivity. (n = 8 WT and 22–24 rTg4510 mice per group; ***p<0.001, Two-way ANOVA followed by Bonferroni's test compared to baseline groups).
Fig 5.
Effects of doxycycline treatment on rTg4510 disease progression.
(A) Brain hyperphosphorylated tau levels were revealed by PHF6 AlphaLISA in rTg4510 mice (n = 22–24 mice/group; ***p < 0.001, t-test). (B) Effects of doxycycline treatment on forebrain weight was measured in both WT and rTg4510 mice (n = 8 WT and 22–24 rTg4510 mice per group, *p < 0.05, **p < 0.01, t-test).
Fig 6.
Effects of OGA inhibitor Thiamet G treatment on rTg4510 disease progression.
(A) LMA was measured at the baseline (2 months of age) and monthly after the onset of treatment (n = 20–21/group; **p < 0.01, ***p < 0.001, Two-way ANOVA followed by Bonferroni's test compared to baseline groups at 2 months of age). (B–D) Thiamet G significantly reduced brain hyperphosphorylated tau levels detected by PHF6 AlphaLISA (B), prevented brain atrophy (C), and reduced CSF total tau levels (D) in rTg4510 mice (n = 21/group; *p < 0.05, **p < 0.01, ***p < 0.001, one-way ANOVA followed by Dunnett’s test compared to vehicle group).