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. 2020 Nov 23;11:5950. doi: 10.1038/s41467-020-19786-7

Fig. 6. TDP-43 impairs spatial memory, colocalizes and interacts with Aβ, and increases microgliosis in APP/PS1ΔE9 mice.

Fig. 6

a, b The spatial learning and memory function of APP/PS1ΔE9 mice were inspected via MWM. The training phase (a) and probe test (b) are shown (buffer, n = 6, TDP-43, n = 8). a For the training phase, the averaged data and s.e.m. are plotted. The data were colored for buffer-injected WT mice (black), TDP-43-injected WT mice (green), buffer-injected APP/PS1∆E9 mice (blue), and TDP-43-injected APP/PS1∆E9 mice (red). Statistical analysis was performed via repeated two-way ANOVA with Bonferroni’s post-hoc test, *p < 0.05, ***p < 0.001 (Buffer-APP/PS1ΔE9 vs. TDP-43-APP/PS1ΔE9 at day 2, p = 0.0190; at day 3, p = 0.0002; at day 4, p = 0.0135; at day 5, p = 0.0002). b For the probe test, the average data and s.e.m. are plotted. Statistical analysis was conducted with one-way ANOVA, Holm-Sidak’s multiple comparisons, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 (In the opposite quadrant, Buffer-WT vs. TDP-43-APP/PS1ΔE9, p = 0.0036; TDP-WT vs. TDP-43-APP/PS1ΔE9, p = 0.0122; Buffer-APP/PS1ΔE9 vs. TDP-43-APP/PS1ΔE9, p = 0.0008; In the target quadrant: Buffer-WT vs. TDP-43-WT, p = 0.0046; Buffer-APP/PS1ΔE9 vs. TDP-43-APP/PS1ΔE9, p < 0.0001; TDP-WT vs. TDP-43-APP/PS1ΔE9, p = 0.0046; buffer-WT vs. TDP-43-APP/PS1ΔE9, p < 0.0001; TDP-WT vs. buffer-APP/PS1ΔE9, p = 0.0046). c Representative immunostaining micrographs in the hippocampus dentate gyrus show that TDP-43 oligomers colocalized with Aβ plaque (arrows) and intraneuronal Aβ (arrowhead; scale bar, 150 μm). Three induvial animals in each group were examined. d The enlarged view of the rectangle in 6c (scale bar, 100 μm). e Representative IP result of Aβ and TDP-43 in the brain fractions of APP/PS1ΔE9 mice injected with TDP-43. Extracellular-enriched and Triton-soluble brain fractions were used. IP was performed using Aβ antibodies and detected by TDP-43 antibodies. Immunoprecipitated TDP-43 was indicated by red arrows and nonspecific bands were indicated by blue asterisks. Four independent experiments were performed. f TDP-43 injection increased microgliosis in the hippocampus dentate gyrus of APP/PS1ΔE9 mice. Representative Iba1 immunostaining micrographs of buffer-injected (n = 5) or TDP-43-injected (n = 4) wild-type mice and buffer-injected (n = 9) or TDP-43-injected (n = 10) APP/PS1ΔE9 mice. The calculated cell density of Iba1-positive microglial cell is shown (scale bar, 30 μm). The averaged data and s.e.m. are plotted. Statistical analysis was performed by two-tailed Mann–Whitney test, *p < 0.05, **p < 0.01 (Buffer-WT vs. TDP-43-WT, p = 0.0159; Buffer-WT vs. TDP-43-APP/PS1ΔE9, p = 0.0043; TDP-43-WT vs. Buffer-APP/PS1ΔE9, p = 0.0238; Buffer-APP/PS1ΔE9 vs.TDP-43-APP/PS1ΔE9, p = 0.0076). Source data are provided as a Source Data file.