|
Figure 6 (A) Tau4R-GFP biosensor zebrafish larvae subjected to TBI and treated with the convulsant 4-AP show no brain puncta. Scale bar = 200 μm. (B) 4-AP significantly reduced (apparently eliminated) the abundance of GFP+ puncta in the brain and spinal cord compared to untreated TBI control. Results from alternative doses and timings of 4-AP are reported in Figure 6—figure supplement 1. The impact of 4-AP on tauopathy appears to be independent of its actions on post-traumatic seizures because reducing the latter with anti-convulsant retigabine (RTG) had no measurable effect. (C-F) Pharmacological inhibition of endocytosis reduced tauopathy following TBI. (C) Blocking endocytosis with Pyrimidyn-7 (P7) treatments significantly inhibited the formation of Tau4R-GFP+ puncta following TBI in zebrafish larvae (***p=0.001). (D) Dyngo 4a treatment significantly reduced Tau aggregates in the spinal cord (**p=0.0025) in a manner similar to P7. (E) 4-AP treatment significantly inhibited the formation of Tau4R-GFP+ puncta in the spinal cord (***p=0.0003) of Tau biosensor line that also express human Tau (0N4R) after traumatic brain injury compared to untreated TBI control group. (F) A notable reduction in Tau aggregates was observed in the same line after treatment with P7 drug. Statistical analysis shows no significance difference (ns, p=0.2223) between groups. n = number of larvae. ****p<0.0001, Kruskal-Wallis ANOVA with Dunn’s multiple comparison test used throughout this Figure.