Fig. 3: SCDi infusion in symptomatic 3xTg mice improves spatial learning and memory without modulating neural stem/progenitor activity or neuronal loss.

a, b Learning and memory in the Morris water maze (WT-D, n = 11; 3xTg-D, n = 12; WT-S, n = 12; 3xTg-S, n = 14). Learning (latency) average of 6 trials/day/mouse (a). Two-way repeated measures ANOVA identified significant time (F(2.539, 114.3) = 77.88, p < 0.0001) and strain (F(3,45) = 3.452, p = 0.0242) effects, with no interaction. Area under the curve (AUC) (inset) showing higher cumulative latency in 3xTg-D group that is not present in the 3xTg-S group (two-way ANOVA, strain effect F(1,45) = 6.363, p = 0.0153, strain/treatment interaction of F(1,45) = 2.634, p = 0.1116), Dunnett’s post-hoc test, p = 0.0177). Memory (platform crossings) (b). Two-way ANOVA showed strain effect (F(1,45) = 5.114, p = 0.0286) and that the 3xTg-D group, but not the WT-S or 3xTg-S groups, was significantly different from the WT-D group (Dunnett’s post-hoc test, p = 0.0351). Representative heatmaps of swim trajectories (right). Error bars represent mean ± SEM. *p ≤ 0.05. c–j Quantification of proliferation and neuroblasts in the DG (c–f) and SVZ (g–j) of 10-month-old WT-D (n = 3), 3xTg-D (n = 5), WT-S (n = 4), and 3xTg-S mice (n = 5). We observed decreased total proliferating cells in the DG (WT-D/3xTg-D, p = 0.005, WT-D/3xTg-S, p = 0.008) (c) and in the SVZ (WT-D/3xTg-D p = 0.008, WT-D/3xTg-S, p = 0.002) (g). No changes were detected in Ki67+/GFAP+ proliferating neural stem cells in the DG (d) or SVZ (h). We found fewer Ki67+/DCX+ proliferating neuroblasts in the DG (WT-D/3xTg-D, p = 0.0009, WT-D/3xTg-S, p = 0.0012) (e) and in the SVZ (WT-D/3xTg-D, p = 0.03, WT-D/3xTg-S, p = 0.01) (i) as well as a decrease in DCX + total neuroblasts in the DG (WT-D/3xTg-D, p = 0.002, WT-D/3xTg-S, p = 0.0002) (f) with no difference in the SVZ (j). No SCDi-mediated change was observed in any of these parameters of neural stem/progenitor activity (two-way ANOVA, Dunnett’s post-hoc test). DG Dentate gyrus, SVZ subventricular zone. Error bars represent mean ± SEM. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. k–n Quantification of Nissl-stained neuron number (k) and granular layer thickness (l) in the DG and neuron number (m) and pyramidal layer thickness in the CA1 (n) of WT-D (n = 5), 3xTg-D (n = 4), WT-S (n = 6), 3xTg-S (n = 5) mice. Note no SCDi-mediated change was observed in neuronal loss parameters (two-way ANOVA, Dunnett’s post-hoc test). Error bars represent mean ± SEM. **p ≤ 0.01. Source data are provided as a Source Data file.