Fig. 4

AAV9 Tau ΔD421 produces hippocampal inflammation and targeted disruption of SSAT increases NeuN expression and reduces tau neuropathology. a–d Representative images and quantification of immunohistochemical analysis of hippocampal and cortical inflammation (Iba1) and NeuN expression in response to 4-month incubation of either AAV9 empty capsid (EC) or AAV9 Tau ΔD421 in 15-month-old nTg and SSAT-/- mice (n = 7–11). Iba1: Simple main effects analysis showed that AAV9 Tau ΔD421 significantly increased inflammation (Iba1) in only the hippocampus (F(1, 36) = 6.823, p = .013). Further, within each genotype, pairwise comparisons revealed a significant difference in hippocampal Iba1 between only the SSAT-/- AAV9 empty capsid and SSAT-/- AAV9 Tau ΔD421 groups (p = .048). NeuN: Simple main effects analysis showed that AAV9 Tau ΔD421 significantly decreased NeuN expression (NeuN) in only the hippocampus (F(1, 35) = 8.973, p = .005). Interestingly, simple main effects analysis also showed that SSAT-/- mice had significantly increased NeuN expression (NeuN) in both the hippocampus (F(1, 39) = 10.343, p = .003) and the cortex (F(1, 35) = 8.100, p = .007), relative to non-transgenic litter-mates. Further, within each genotype, pairwise comparisons revealed a significant difference in hippocampal NeuN between only the SSAT-/- AAV9 empty capsid and SSAT-/- AAV9 Tau ΔD421 groups (p = .013). e–h Representative images and quantification of immunohistochemical analysis of hippocampal (CA3) and anterior cortex (ACX) tau neuropathology in response to 4-month incubation of either AAV9 empty capsid (EC) or AAV9 Tau ΔD421 in 15-month old nTg and SSAT-/- mice (n = 7–11). HT7: Simple main effect analysis showed that AAV9 Tau ΔD421 significantly increased total tau (HT7) in both the CA3 of the hippocampus (F(1, 34) = 55.939, p = .000) and the anterior cortex (ACX; F(1, 35) = 57.020, p = .000). Importantly, the level of total tau was not significantly different between nTg and SSAT-/- mice, ensuring treatment was equal across groups. pSer199/202: Simple main effects analysis showed that AAV9 Tau ΔD421 significantly increased Tau pSer199/202 in the CA3 (F(1, 36) = 29.869, p = .000) and the ACX (F(1, 34) = 36.192, p = .000). Interestingly, in the CA3, there was also a main effect of genotype (F(1, 36) = 4.114, p = .05), and pairwise comparison revealed a significant difference between nTg AAV9 Tau ΔD421 and SSAT-/- AAV9 Tau ΔD421 mice (p = .010), identifying a protective effect of SSAT disruption in CA3 Tau pSer199/202. Further, in the ACX, there was a significant interaction of factors (F(1, 34) = 3.994, p = .05), and pairwise comparison again revealed a significant difference between nTg AAV9 Tau ΔD421 and SSAT-/- AAV9 Tau ΔD421 mice (p = 0.17), identifying a protective effect of SSAT disruption in ACX Tau pSer 199/202. AT8: Simple main effects analysis showed that AAV9 Tau ΔD421 significantly increased phosphorylated paired helical filament tau (PHF; AT8) in both the CA3 (F(1, 36) = 32.677, p = .000) and ACX (F(1, 33) = 22.792, p = .000). No effect of genotype or interaction of factors was detected. 2 × 2 Factorial analysis of variance (ANOVA), followed by pairwise comparisons using Fisher’s PLSD. *p < .05; asterisks indicate the main effect of treatment and main effect of genotype, and ampersands indicate the interaction of genotype and treatment. Data is represented by means ± S.E.M.