Fig. 4

Neurodegeneration in the hippocampus of dox-administered hTau368 mice. a Volcano plots illustrating upregulated (red) or downregulated (blue) genes in the hippocampus of homozygous hTau368 mice with 2 months of dox treatment compared with Veh. FDR-adjusted P < 0.05 and fold change ≥ 1.5 were considered significant in RNA-seq analysis; n = 3 mice in each group. b-e GESA and KEGG analyses revealed that DEGs were enriched in biological processes involving cell–cell/cell–matrix interactions (ECM-receptor interaction, cell adhesion, tight junction, neuroactive ligand-receptor interaction), PI3K-Akt signaling pathway and neurodegeneration. f KEGG pathway relationship network of DEGs. Only the top 10 pathways with the largest number of genes are displayed. Blue dots represent individual genes in each KEGG pathway (purple rectangles) annotated by dashed black circles g Dox-treated homozygous hTau368 mice showed axonal swelling and less synaptic contacts. Right panels are zoom-in views of the dashed yellow rectangles in the left panels; red arrows indicate synaptic contacts; n = 12 views from 3 mice per group. Unpaired Student’s t-test, *P < 0.05, ***P < 0.001. h, i Dox-treated hemi- and homozygous hTau368 mice had lower levels of PSD95 in the hippocampal tissue. One-way ANOVA followed by Tukey's multiple comparisons tests, **P < 0.01, ***P < 0.001, compared with the Veh group; n = 3–4 mice in each group. j, k Dox-treated homozygous hTau368 mice showed decreased number of DCX-labeled immature neurons in the hippocampus. Unpaired Student’s t-test, ***P < 0.001; n = 3 sections from 3 mice per group