Figure 7. Cyclo-dPAKKR reduces demyelination and axonal degeneration in a p75NTR-dependent manner. Histologic analyses of longitudinal sciatic nerve sections of EAN mice following daily treatment of either cyclo-dPAKKR (10 mg/kg) or control peptide (cyclo-AdPAKKR, 10 mg/kg) in p75NTR HET or WT littermate control mice from day 1. All tissues were collected at day 23 (disease peak; data: mean ±SEM, 95% confidence interval, ANOVA with Tukey’s post hoc testing n = 3 mice/genotype/group, *p < 0.05, **p < 0.01, ***p < 0.001). A, B, Representative SCoRe images (A) and quantification (B) of SCoRe signal as a percentage of total area measured. WT mice treated with cyclo-dPAKKR display a greater percentage area of SCoRe reflected signal than control peptide, indicating more myelinated axons. Cyclo-dPAKKR exerts no significant influence on HET mice compared with control peptide (scale bar, 200 μm). C, D, Representative images (C) of Caspr immunostaining and quantification (D) of node distance between adjacent Caspr+ paranodes. WT mice treated with cyclo-dPAKKR demonstrate significantly shorter mean node distance compared with mice treated with control peptide. Cyclo-dPAKKR exerts no significant influence on HET mice compared with control peptide (scale bar, 1 μm, minimum 70 nodes per mouse). E, F, Representative images (E) of APP and βIII-tubulin double immunostaining and quantitation (F) of the percentage of APP+ axonal area colocalizing with βII-tubulin. Cyclo-dPAKKR treatment significantly reduced the percentage of APP+ colocalization with βII-tubulin compared with the control peptide in WT, but not in HET mice (scale bar, 5 μm; scale in inset, 20 μm).