APP and Aβ levels are not dependent on PrP^C. a–f, Immunoblot analysis of soluble brain extracts (a–c, f) or detergent-extracted particulate fractions (d) or guanidinium-solubilized material (e) with anti-Aβ 6E10 antibody (a, c–e), anti-APP 22C11 antibody (b), or anti-PrP^C 6D11 antibody (f). Genotype is indicated at the top of each blot for separate mice. The migration of MW standards is shown at the left. g, Densitometric analysis of immunoblot signals from experiments as in a–f. Data are mean ± SEM for n = 5–12 mice per genotype. h, i, Immunofluorescent detection of Aβ in a parasagittal section of the anterior half of a APPswe/PSen1ΔE9 transgenic mouse brain at 12 months of age of the Prnp+/+ (h) or Prnp−/− (i) genotype.

Serotonin axons and synaptic markers are preserved in APPswe/PSen1ΔE9 mice lacking PrP^C. a, Anti-GFAP immunohistology of parasagittal brain sections was scored for astrocytic area in the anterior half of the cerebral cortex. Data are mean ± SEM for n = 10 mice per genotype. b, Parasagittal sections of cerebral cortex from mice of the indicated genotypes were stained with anti-5-HT. Projections of 30 µm confocal Z-stacks are shown. Note the reduced fiber length in the APPswe/PSen1ΔE9 sample. Scale bar, 50 µm. c, The 5-HT-immunoreactive fiber length in the parasagittal plane from images as in b was measured. Data are mean ± SEM for n = 10–16 mice per genotype. *p < 0.05, one-way ANOVA with post hoc comparisons as indicated; n.s., no significant difference. d, Cerebral cortex from mice of the indicated genotypes was stained with anti-synaptophysin antibody and imaged by confocal microscopy with a 100× objective. Scale bar, 10 µm. e, f, The fractional area of immunoreactive puncta from images as in d is reported as a function of genotype. Sections were stained with anti-synaptophysin (e) or anti-PSD-95 (f). Data are mean ± SEM for n = 4–8 sites from each of 9–10 mice per genotype. *p < 0.05, one-way ANOVA with post hoc comparisons.

Survival of APP-PSen mice improved by absence of PrP^C. Survival of wild-type and APPswe/PSen1ΔE9 transgenic mice with and without PrP^C expression. Survival of the APPswe/PSen1ΔE9 mice is significantly shorter than each of the other three genotypes by the Wilcoxon statistic (p < 0.005).

Deletion of PrP^C expression rescues spatial learning and memory in APPswe-PSen1ΔE9 transgenic mice. a, Spatial learning is plotted as the latency to find a hidden platform in the Morris water maze at 12 months of age. After the first set of swim trials, the platform location was reversed for the second set of trials. At a later time, after the probe trial, latency to reach a visible platform was scored. Data are mean ± SEM for these groups: C57BL/6, n = 19 (8 male, 11 female); Prnp−/− n = 15 (7 male, 8 female); APP-PSen n = 11 (6 male, 5 female); APP-PSen, Prnp−/− n = 20 (11 male, 9 female). Performance differed by genotype across trial blocks 5–6 and 9–12 (two-way RM-ANOVA: APP-PSen by Prnp interaction, p < 0.015; APP-PSen, p < 0.001; Prnp, p < 0.001). For the indicated Tukey post hoc pairwise comparisons, the APP-PSen group differed from each of the other three groups (p < 0.001), but none of the other genotypes differed significantly from one another. b, The performance of the APPswe/PSen1ΔE9 transgenic mice with and without PrP^C expression from trial blocks 11–12 of a is separated by sex. The latencies are reduced in the Prnp−/− groups compared to the Prnp+/+ groups, *p < 0.05, two-tailed Student’s t test. c–f, Mice of each genotype were tested for spatial learning at 3 months, and the data are compared to the 12 month performance curves replotted from a. By RM-ANOVA, only the APP-PSen group differed significantly (p < 0.05) between age groups. Data are mean ± SEM for n = 11–20 mice per group. g, The performance of the APPswe/PSen1ΔE9 transgenic mice with and without PrP^C expression from trial blocks 11–12 of d–f is separated by age. The latencies are reduced in the Prnp−/− groups compared to the Prnp+/+ at 12 months but not 3 months, *p < 0.05, two-tailed Student’s t test. h, Two days after the second set of hidden platform learning trials from a, a 60 s probe trial was conducted. The swim track of one representative mouse from each of the four genotypes is illustrated. A small circle indicates the learned platform location. i, j, The time spent at the site of the previous platform location (i) and crosses of the previous platform location (j) are shown. Data are mean ± SEM for n = 11–20 mice per group. *p < 0.05, one-way ANOVA with post hoc comparison to the WT group.