PMC

Amyloid plaques are specific to APP/PS1 mice at 6 months of age. Immunohistochemistry against Aβ reveals widespread amyloid pathology in 6-month-old APP/PS1 mice (A), whereas no Aβ plaques are present in APP single-transgenic mice at this age (B). Scale bars, 150 μm.

Proliferation of hippocampal progenitor cells is unchanged by transgenic expression of mutant APP and/or PS1. A–D, Ki67 immunostaining in the DG is similar in all four genotypes. Nuclear Fast Red was used as a counterstain to identify morphological boundaries of the GCL and SGZ. Scale bars, 30 μm. E, The number of Ki67+ cells in the DG was counted for each genotype (mean ± SEM; n = 4 for each group). The number of Ki67+ cells is similar across all four genotypes; overproduction of APP/Aβ had no significant effect on progenitor cell proliferation in the SGZ.

Overproduction of APP/Aβ specifically diminishes survival of newborn neurons in APP and APP/PS1 mice. A–C, E–G, Confocal analysis was used to score the coexpression of NeuN (green; C, G) and S100β (blue; B, F) in BrdU+ cells (red; A, E) from each genotype. D, H, Arrows in the merged images indicate BrdU+/NeuN+ neurons (D, H), the asterisk identifies a BrdU+/S100β+ astrocyte (H), and arrowheads indicate BrdU+ cells coexpressing neither marker (D). I, Distribution of phenotypes in BrdU+ cells by genotype. Compared with NTG, a significantly smaller number of BrdU+ cells colabel with NeuN (green) in the hippocampus of both APP and APP/PS1 transgenic mice (***p < 0.01 vs NTG; ANOVA with Tukey's post hoc). In contrast, the number of newborn S100β+ astrocytes (blue) and newborn cells expressing neither neuronal nor glial markers (red) is unchanged by overproduction of APP/Aβ. Error bars indicate SEM.

Overproduction of APP/Aβ exacerbates cell death of newborn neurons as they approach maturity. A–C, Confocal analysis was used to score the coexpression of NeuN (blue; C) and DCX (green; B) in BrdU+ cells (red; A) in APP/PS1 and NTG mice. D, The arrowhead in the merged image identifies a BrdU+/DCX+/NeuN− immature neuron. E, The number of BrdU+ cells coexpressing the immature neuronal precursor marker DCX (green) is smaller in APP/PS1 than in NTG mice (*p < 0.05; ANOVA with Tukey's post hoc). The decrease in BrdU+ cells coexpressing the postmitotic neuronal marker NeuN (blue) in APP/PS1 mice is even more dramatic than the loss of DCX+ cells (***p < 0.001; ANOVA with Tukey's post hoc). In contrast, a similar number of newborn cells express neither marker (red) in APP/PS1 and NTG mice. Error bars indicate SEM.

Late survival of newborn cells in the adult DG is dramatically reduced in APP/PS1 mice. A–D, Thirty days after the final BrdU injection, the number of BrdU-immunoreactive cells is noticeably diminished in the DG of double-transgenic APP/PS1 mice. Nuclear Fast Red was used as a counterstain to identify morphological boundaries of the GCL and SGZ. Scale bars, 30 μm. E, The absolute number of BrdU+ cells in the DG is shown for each genotype (mean ± SEM; n = 10–12 per group). Overproduction of APP/Aβ reduced the number of labeled cells surviving 30 d after the final BrdU injection in APP/PS1 double-transgenic animals (***p < 0.001 vs NTG; ^###p < 0.001 vs PS1; ANOVA with Tukey's post hoc). Neither APP nor PS1 by themselves had any effect on the survival of newborn DG cells compared with NTG (APP vs PS1, ^#p < 0.05).

Short-term survival of newborn cells in the adult DG is not affected by APP/Aβ overproduction. A–D, One day after the last of 12 daily BrdU injections, BrdU immunostaining in the DG is similar in all four genotypes. Nuclear Fast Red was used as a counterstain to identify morphological boundaries of the GCL and SGZ. Scale bars, 30 μm. E, The absolute number of BrdU+ cells in the DG is shown for each genotype (mean ± SEM; n = 9–12 for each group). Overproduction of APP/Aβ had no significant effect on the number of BrdU+ cells that were labeled 1–12 d earlier. Similarly, transgenic expression of mutant PS1 had no effect on early survival within the DG, either alone or when coexpressed with APPswe.