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. 2014 Feb 16;127(5):667–683. doi: 10.1007/s00401-014-1254-6

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© Springer-Verlag Berlin Heidelberg 2014

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Fig. 2 — Time-dependent progression of ^P301SBE-induced hippocampal tau pathology. a Representative images showing PG-5-positive tau pathology in the hippocampus (bregma −2.50) of human P301S tau transgenic mice 1 day, 2 weeks, 1 month, 2 months and 2.5 months after the infusion with ^P301SBE, compared to P301S tau mice 2.5 months after the infusion with ^WTBE/PBS. Insets show PG-5 immunohistochemistry and Gallyas silver staining in the CA1 region (performed on adjacent serial sections); those on the right show the infused side and those on the left the contralateral side. Tau pathology was absent at 1 day post-infusion, but mild infusion-related tissue damage was visible on the infused side (indicated by asterisk). From 2 weeks post-infusion, PG-5-positive tau pathology increased in a time-dependent manner on the infused side; neuronal inclusions became more strongly PG-5 positive, were associated with neuropil threads and became increasingly Gallyas silver positive. Similar pathological changes occurred on the contralateral side 1 month post-infusion, where the pathology was comparatively less severe. In contrast, tau pathology was only sparse in the infused and contralateral hippocampus of ^WTBE mice, even 2.5 months post-infusion. b The density of PG-5-positive neurons in the hippocampus showed an age-associated increase on the infused and contralateral sides. From 2 weeks post-infusion, the density of PG-5-positive neurons was significantly (P < 0.05) increased in the infused hippocampus of ^P301SBE mice when compared with ^WTBE/PBS-infused mice 2.5 months post-infusion; similar results were obtained on the contralateral side, but only at 2 months post-infusion. c To investigate the relative proportion of PG-5-positive, silver-negative tau inclusions (pre-tangles) versus PG-5-positive and silver-positive inclusions (NFTs), the number of Gallyas-positive neurons in the CA1 region was expressed as the percentage of the number of PG-5-positive neurons quantified in the same region, but on an adjacent serial section. At 2 weeks post-infusion, the majority of tau inclusions in ^P301SBE-infused mice were pre-tangles, whereas by 2.5 months both the infused and contralateral hippocampi contained predominantly NFTs. In contrast, pre-tangles predominated in PBS-infused mice, even 2.5 months post-infusion. Comparison of ^P301SBE and PBS groups at 2.5 months post-infusion showed a significant increase in NFTs in the former. Statistics: Groupwise comparison, one-way ANOVA with Dunnett’s post hoc test (b) and one-way ANOVA with Bonferroni’s post hoc test (c); pairwise comparison, Student’s t test (c). BE brain extract, WT wild type, d day, w weeks, m month; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Scale bars: a, 1 mm; insets, 100 µm

Fig. 2 — Time-dependent progression of ^P301SBE-induced hippocampal tau pathology. a Representative images showing PG-5-positive tau pathology in the hippocampus (bregma −2.50) of human P301S tau transgenic mice 1 day, 2 weeks, 1 month, 2 months and 2.5 months after the infusion with ^P301SBE, compared to P301S tau mice 2.5 months after the infusion with ^WTBE/PBS. Insets show PG-5 immunohistochemistry and Gallyas silver staining in the CA1 region (performed on adjacent serial sections); those on the right show the infused side and those on the left the contralateral side. Tau pathology was absent at 1 day post-infusion, but mild infusion-related tissue damage was visible on the infused side (indicated by asterisk). From 2 weeks post-infusion, PG-5-positive tau pathology increased in a time-dependent manner on the infused side; neuronal inclusions became more strongly PG-5 positive, were associated with neuropil threads and became increasingly Gallyas silver positive. Similar pathological changes occurred on the contralateral side 1 month post-infusion, where the pathology was comparatively less severe. In contrast, tau pathology was only sparse in the infused and contralateral hippocampus of ^WTBE mice, even 2.5 months post-infusion. b The density of PG-5-positive neurons in the hippocampus showed an age-associated increase on the infused and contralateral sides. From 2 weeks post-infusion, the density of PG-5-positive neurons was significantly (P < 0.05) increased in the infused hippocampus of ^P301SBE mice when compared with ^WTBE/PBS-infused mice 2.5 months post-infusion; similar results were obtained on the contralateral side, but only at 2 months post-infusion. c To investigate the relative proportion of PG-5-positive, silver-negative tau inclusions (pre-tangles) versus PG-5-positive and silver-positive inclusions (NFTs), the number of Gallyas-positive neurons in the CA1 region was expressed as the percentage of the number of PG-5-positive neurons quantified in the same region, but on an adjacent serial section. At 2 weeks post-infusion, the majority of tau inclusions in ^P301SBE-infused mice were pre-tangles, whereas by 2.5 months both the infused and contralateral hippocampi contained predominantly NFTs. In contrast, pre-tangles predominated in PBS-infused mice, even 2.5 months post-infusion. Comparison of ^P301SBE and PBS groups at 2.5 months post-infusion showed a significant increase in NFTs in the former. Statistics: Groupwise comparison, one-way ANOVA with Dunnett’s post hoc test (b) and one-way ANOVA with Bonferroni’s post hoc test (c); pairwise comparison, Student’s t test (c). BE brain extract, WT wild type, d day, w weeks, m month; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Scale bars: a, 1 mm; insets, 100 µm