Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Jul 20;31(29):10427-31.
doi: 10.1523/JNEUROSCI.1459-11.2011.

Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic mice

Moustapha Cissé  1 , Pascal E Sanchez, Daniel H Kim, Kaitlyn Ho, Gui-Qiu Yu, Lennart Mucke
Affiliations

Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic mice

Moustapha Cissé et al. J Neurosci. .

Erratum in

  • J Neurosci. 2011 Sep 28;31(39):14046

Abstract

Previous studies suggested that the cellular prion protein (PrP(c)) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Specifically, amyloid-β (Aβ) oligomers were proposed to cause synaptic and cognitive dysfunction by binding to PrP(c). To test this hypothesis, we crossed human amyloid precursor protein (hAPP) transgenic mice from line J20 onto a PrP(c)-deficient background. Ablation of PrP(c) did not prevent the premature mortality and abnormal neural network activity typically seen in hAPPJ20 mice. Furthermore, hAPPJ20 mice with or without PrP(c) expression showed comparably robust abnormalities in learning and memory and in other behavioral domains at 6-8 months of age. Notably, these abnormalities are not refractory to therapeutic manipulations in general: they can be effectively prevented by interventions that prevent Aβ-dependent neuronal dysfunction also in other lines of hAPP transgenic mice. Thus, at least in this model, PrP(c) is not an important mediator of Aβ-induced neurological impairments.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Ablation of PrPc in hAPPJ20 mice does not prevent their behavioral abnormalities in the elevated plus maze, open field, and object recognition test. A–C, Six- to eight-month-old Prnp+/+ and Prnp−/− mice with or without hAPP (n = 10–15 mice per genotype) were tested in the indicated behavioral paradigms. A, In the elevated plus maze, mice with hAPP spent more time in the open arms than mice without hAPP. hAPP/Prnp+/+ mice and hAPP/Prnp−/− mice showed a similar level of disinhibition. Two-way ANOVA revealed a significant effect of hAPP (p < 0.0001), but not of Prnp (p = 0.748), and no interaction between hAPP and Prnp (p = 0.607). B, In the open field, mice with hAPP were hyperactive compared to mice without hAPP. The subtle difference between hAPP/Prnp+/+ mice and hAPP/Prnp−/− mice was not significant even by one-tailed t test (p = 0.132). Two-way ANOVA revealed a significant effect of hAPP (p < 0.0001), but not of Prnp (p = 0.445), and no interaction between hAPP and Prnp (p = 0.223). C, Mice were analyzed in the novel object recognition test. Unlike littermates without hAPP, hAPPJ20/Prnp+/+ mice and hAPPJ20/Prnp−/− mice failed to spend more time with the novel than with the familiar object in test sessions. Two-way ANOVA of the average ratios of time spent with the novel versus the familiar object revealed a significant effect of hAPP (p < 0.005), but not of Prnp (p = 0.322), and no interaction between hAPP and Prnp (p = 0.561). *p < 0.05, **p < 0.005, ***p < 0.0005 versus mice without hAPP of the same Prnp genotype (Tukey test) (A, B) or versus familiar object (paired, two-tailed t test) (C). Data represent means ± SEM.
Figure 2.
Figure 2.
PrPc ablation in hAPPJ20 mice does not prevent deficits in spatial learning and memory. Six- to eight-month-old Prnp+/+ and Prnp−/− mice with or without hAPP (n = 10–15 mice per genotype) were trained in the Morris water maze for 4 d. Time (latency) and distance swum (data not shown) before reaching the platform were recorded. A probe trial (platform removed) was conducted 24 h after the last training. A, hAPP/Prnp+/+ and hAPP/Prnp−/− mice learned this task more poorly than mice without hAPP. Two-way repeated-measures ANOVA revealed a significant effect of hAPP (p < 0.0001), but not of Prnp (p = 0.0613), and no interaction between hAPP and Prnp (p = 0.632). B, C, During the probe trial, mice without hAPP, but not mice with hAPP, favored the target quadrant (B) and crossed the target location more often than corresponding places in nontarget quadrants (C). Two-way ANOVA of these data revealed a significant effect of hAPP (B, p < 0.05; C, p < 0.005), but not of Prnp (B, p = 0.8691; C, p = 0.647), and no interaction between hAPP and Prnp (B, p = 0.4620; C, p = 0.281). D, During the probe trial, mice with hAPP took longer to reach the target location than mice without hAPP. Two-way ANOVA revealed a significant effect of hAPP (p < 0.0001), but not of Prnp (p = 0.238), and no interaction between hAPP and Prnp (p = 0.483). One-way ANOVA and Bonferroni test revealed a significant difference between hAPP/Prnp+/+ and hAPP/Prnp−/− mice (p < 0.05). *p < 0.05, **p < 0.005, ***p < 0.0005 versus nontarget quadrants by paired, two-way t test (B, C) or versus mice without hAPP of the same Prnp genotype by Tukey test (D). Data represent means ± SEM.
Figure 3.
Figure 3.
Ablation of PrPc worsens early mortality in hAPPJ20 mice. Death and survival were monitored in a total of 169 mice. A, Percentage of mice born by genotype. The difference between the number of mice obtained and expected for each genotype, based on Mendelian principles of inheritance (12.5%), was not significant (χ2 = 0.72; p = 0.86). B, Premature death reported from P0 to P27. Mortality tended to be higher in hAPP than NTG mice (one-sided χ2 = 1.9, p = 0.07), independently of their Prnp genotype (two-sided χ2 = 0.28, p = 0.59). C, Kaplan–Meier survival plot shows more mice with hAPP died prematurely than mice without hAPP after weaning (p < 0.01, Mantel–Cox test). Premature mortality was greater in hAPP/Prnp−/− mice than in hAPP/Prnp+/+ mice (p < 0.001, Mantel–Cox test).
Figure 4.
Figure 4.
Ablation of PrPc worsens spontaneous epileptiform activity in hAPPJ20 mice. EEG was recorded over both parietal cortices for 48 h in 6- to 8-month-old mice (n = 3–6 mice per genotype). A, In contrast to mice lacking hAPP, hAPP/Prnp+/+ and hAPP/Prnp−/− mice showed frequent epileptiform spikes (see gray arrowheads). L, Left; R, right. B, Quantification of epileptiform spikes. Two-way ANOVA revealed effects of hAPP (p < 0.0001) and Prnp (p = 0.03), and an interaction between hAPP and Prnp (p = 0.036). *p < 0.01, ***p < 0.0001 versus mice without hAPP or as indicated by bracket (Bonferroni post hoc test). Values are means ± SEM.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aguzzi A, Baumann F, Bremer J. The prion's elusive reason for being. Annu Rev Neurosci. 2008;31:439–477. - PubMed
    1. Ashe KH, Zahs KR. Probing the biology of Alzheimer's disease in mice. Neuron. 2010;66:631–645. - PMC - PubMed
    1. Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G. Synthetic amyloid-{beta} oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci U S A. 2010;107:2295–2300. - PMC - PubMed
    1. Büeler H, Fischer M, Lang Y, Bluethmann H, Lipp H, DeArmond S, Prusiner S, Aguet M, Weissmann C. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature. 1992;356:577–582. - PubMed
    1. Calella AM, Farinelli M, Nuvolone M, Mirante O, Moos R, Falsig J, Mansuy IM, Aguzzi A. Prion protein and Abeta-related synaptic toxicity impairment. EMBO Mol Med. 2010;2:306–314. - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources