Early intervention of tau pathology prevents behavioral changes in the rTg4510 mouse model of tauopathy

<div><p>Although tau pathology, behavioral deficits, and neuronal loss are observed in patients with tauopathies, the relationship between these endpoints has not been clearly established. Here we found that rTg4510 mice, which overexpress human mutant tau in the forebrain, develop progressive age-dependent increases in locomotor activity (LMA), which correlates with neurofibrillary tangle (NFT) pathology, hyperphosphorylated tau levels, and brain atrophy. To further clarify the relationship between these endpoints, we treated the rTg4510 mice with either doxycycline to reduce mutant tau expression or an O-GlcNAcase inhibitor Thiamet G, which has been shown to ameliorate tau pathology in animal models. We found that both doxycycline and Thiamet G treatments starting at 2 months of age prevented the progression of hyperactivity, slowed brain atrophy, and reduced brain hyperphosphorylated tau. In contrast, initiating doxycycline treatment at 4 months reduced neither brain hyperphosphorylated tau nor hyperactivity, further confirming the relationship between these measures. Collectively, our results demonstrate a unique behavioral phenotype in the rTg4510 mouse model of tauopathy that strongly correlates with disease progression, and that early interventions which reduce tau pathology ameliorate the progression of the locomotor dysfunction. These findings suggest that better understanding the relationship between locomotor deficits and tau pathology in the rTg4510 model may improve our understanding of the mechanisms underlying behavioral disturbances in patients with tauopathies.</p></div

LMA in 5-month-old rTg4510 mice correlates with brain atrophy and NFT pathology.

<p>(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).</p

Effects of OGA inhibitor Thiamet G treatment on rTg4510 disease progression.

<p>(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).</p

Effects of doxycycline treatment on rTg4510 disease progression.

<p>(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).</p

Correlation between LMA and brain hyperphosphorylated tau levels.

<p>(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.</p

Effects of doxycycline treatment on progression of hyperactivity in rTg4510 mice are age-dependent.

<p>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).</p

rTg4510 mice exhibit increased LMA in an age-dependent manner.

<p>(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).</p