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. 2019 Jun 29;11:58. doi: 10.1186/s13195-019-0507-y

Fig. 5.

Fig. 5

AAV9 Tau ΔD421 produces robust hippocampal tau neuropathology; SSAT disruption prevents the accumulation of high molecular weight tau phospho-epitopes. a–i Representative images and quantification of western blot analysis of hippocampal tau neuropathology, exogenous Tau ΔD421, exogenous total tau (HT7), exogenous and endogenous total tau (Tau-5), pS199/202, tau-paired helical filament (Tau PHF; AT8), and pS396, 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 = 3–5). Tau ΔD421: Simple main effects analysis showed that AAV9 Tau ΔD421 significantly increased Tau ΔD421 (F(1, 16) = 24.925, p = .000). Importantly, the level of Tau ΔD421 was not significantly different between nTg and SSAT-/- mice, ensuring treatment was equal across groups. No main effect of genotype or interaction of factors was detected on Tau ΔD421. Total tau (HT7): Simple main effects analysis showed that AAV9 Tau ΔD421 significantly increased total tau (HT7) (F(1, 16) = 29.585, p = .000). Importantly, the level of total tau was not significantly different between nTg and SSAT-/- mice, ensuring treatment was equal across groups. No main effect of genotype or interaction of factors was detected on total tau (HT7). Tau-5: An interaction of factors was detected (F(1, 16) = 4.657, p = .046) on Tau-5, indicating the levels of Tau-5 are dependent on genotype, with targeted SSAT disruption decreasing Tau-5 levels. Tau pS199/202: Simple main effects analysis showed that AAV9 Tau ΔD421 significantly increased monomeric (F(1, 16) = 26.621, p = .000) and high molecular weight (HMW; F(1, 16) = 5.143, p = .038) Tau pS199/202. No main effect of genotype or interaction of factors was detected on pS199/202. AT8: Simple main effects analysis showed that AAV9 Tau ΔD421 significantly increased Tau PHF (AT8; F(1, 16) = 27.482, p = .000). No main effect of genotype or interaction of factors was detected on AT8. Tau pS396: Simple main effects analysis showed that AAV9 Tau ΔD421 significantly increased monomeric (F(1, 16) = 15.084, p = .001) Tau pS396; however, pairwise comparisons revealed that AAV9 Tau ΔD421 only significantly increased monomeric pS396 in the nTg genotype (p = .003) and not in the SSAT-/- genotype (p = .073) indicating an impact of SSAT on monomeric Tau pS396. This notion is supported by the significant pairwise comparison between nTg AAV9 Tau ΔD421 and SSAT-/-0 AAV9 Tau ΔD421 groups (p = .048). Further, there was an interaction of factors on HMW Tau pS396 (F(1, 16) = 25.183, p = .000), indicating the levels of HMW Tau pS396 are dependent on genotype, with targeted SSAT disruption decreasing HMW pS396 levels. This is supported by the lack of significant pairwise comparison between SSAT-/- AAV9 empty capsid and SSAT-/- AAV9 Tau ΔD421 (p = .09), and the significant pairwise comparison between nTg AAV9 Tau ΔD421 and SSAT-/- AAV9 Tau ΔD421, again with SSAT-/- decreasing HMW pS396 levels. 2 × 2 Factorial analysis of variance (ANOVA), followed by pairwise comparisons using Fishers PLSD. *p < .05; asterisks indicate the main effect of treatment and main effect of genotype, ampersands indicate the interaction of genotype and treatment, and number signs indicate the pairwise comparison within genotype. Data is represented by means ± S.E.M.