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. 2014 Mar 19;34(12):4260–4272. doi: 10.1523/JNEUROSCI.3192-13.2014

Figure 8.

Figure 8.

Extracellular and peripheral clearance of tau oligomers by TOMA. A–D, In vivo imaging demonstrates that a fraction of TOMA injected into the tail vein crosses the BBB and binds to tau oligomers in the 8-month-old P301L brain and spinal cord. A, TOMA at the injection site in 8-month-old wild-type-C57 and P301L mice at time 0; animals were imaged immediately after the injection. B, Animals imaged 4 h after injection showed retention of TOMA only in the brains of P301L animals, whereas TOMA was cleared from the wild-type animals. C–D, To confirm that TOMA entered the CNS, we imaged brain and spinal cord sections derived from cryotome cross-sectioning of P301L and wild-type brains and spinal cords extracted from animals killed 4 h after TOMA injection. E–J, Biotinylated TOMA antibody (30 μg/animal) was injected into the tail veins of 8-month-old P301L mice. E–H, Representative images of brain sections stained with streptavidin-peroxidase demonstrate that biotinylated TOMA antibody crosses the BBB and remains in hippocampus 2, 6, and 24 h after injection. Scale bar, 30 μm. I, Dot blot analyses of PBS soluble fractions from brain homogenates of mice injected with biotinylated TOMA confirmed the presence of the biotinylated antibody in the brain compared with the control (brain homogenate from P301L mouse injected with unlabeled TOMA). A 0.5 μl aliquot of biotinylated-TOMA was used as a positive control. J, Quantification of the dot intensities. ★★★p < 0.0005; ★★p < 0.001, one-way ANOVA, Bonferroni post hoc comparison. K–M, Detailed quantitative analysis of the short-term effects of intravenous TOMA injection on the levels of both oligomeric and total tau in the serum. K, Tau oligomers were quantified by direct ELISA using T22 before and at different time points shortly after TOMA injections in 8-month-old P301L and wild-type mice. The effects of TOMA were rapid and a significant increase in tau oligomer levels occurred in the serum, peaking at 1 h. By 24 h, levels began to decline. L, Levels of total tau measured by direct ELISA using HT7 confirmed TOMA effects and correlated with the changes observed for tau oligomers. ★★★★p < 0.0001; ★★★p < 0.001, two-way ANOVA, Bonferroni post hoc comparison. M, Tau oligomer reduction in brain homogenates measured 168 h after TOMA injection. ★★★p < 0.0003; ★★p < 0.001, one-way ANOVA, Bonferroni post hoc comparison. Bars represent means and error bars SEM.