Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Persistence of Aβ seeds in APP null mouse brain


Cerebral β-amyloidosis is induced by inoculation of Aβ seeds into APP transgenic mice, but not into App−/− (APP null) mice. We found that brain extracts from APP null mice that had been inoculated with Aβ seeds up to 6 months previously still induced β-amyloidosis in APP transgenic hosts following secondary transmission. Thus, Aβ seeds can persist in the brain for months, and they regain propagative and pathogenic activity in the presence of host Aβ.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Aβ seed persistence in various murine hosts.
Figure 2: Aβ seed persistence in App−/− mice for up to 6 months.


  1. Jucker, M. & Walker, L.C. Nature 501, 45–51 (2013).

    Article  CAS  Google Scholar 

  2. Meyer-Luehmann, M. et al. Science 313, 1781–1784 (2006).

    Article  CAS  Google Scholar 

  3. Eisele, Y.S. et al. Science 330, 980–982 (2010).

    Article  CAS  Google Scholar 

  4. Langer, F. et al. J. Neurosci. 31, 14488–14495 (2011).

    Article  CAS  Google Scholar 

  5. Eisele, Y.S. et al. Proc. Natl. Acad. Sci. USA 106, 12926–12931 (2009).

    Article  CAS  Google Scholar 

  6. Fritschi, S.K. et al. Acta Neuropathol. 128, 477–484 (2014).

    Article  CAS  Google Scholar 

  7. Prusiner, S.B. Annu. Rev. Genet. 47, 601–623 (2013).

    Article  CAS  Google Scholar 

  8. Aguzzi, A. & Falsig, J. Nat. Neurosci. 15, 936–939 (2012).

    Article  CAS  Google Scholar 

  9. Morales, R., Callegari, K. & Soto, C. Virus Res. 207, 106–112 (2015).

    Article  CAS  Google Scholar 

  10. Büeler, H. et al. Cell 73, 1339–1347 (1993).

    Article  Google Scholar 

  11. Prusiner, S.B., Groth, D., Serban, A., Stahl, N. & Gabizon, R. Proc. Natl. Acad. Sci. USA 90, 2793–2797 (1993).

    Article  CAS  Google Scholar 

  12. Sailer, A., Bueler, H., Fischer, M., Aguzzi, A. & Weissmann, C. Cell 77, 967–968 (1994).

    Article  CAS  Google Scholar 

  13. Rupp, N.J., Wegenast-Braun, B.M., Radde, R., Calhoun, M.E. & Jucker, M. Neurobiol. Aging 32, 2324.e1–2324.e6 (2011).

    Article  Google Scholar 

  14. Stalder, M. et al. Am. J. Pathol. 154, 1673–1684 (1999).

    Article  CAS  Google Scholar 

  15. Mackenzie, I.R., Hao, C. & Munoz, D.G. Neurobiol. Aging 16, 797–804 (1995).

    Article  CAS  Google Scholar 

  16. Probst, A., Basler, V., Bron, B. & Ulrich, J. Brain Res. 268, 249–254 (1983).

    Article  CAS  Google Scholar 

  17. Safar, J.G. et al. J. Gen. Virol. 86, 2913–2923 (2005).

    Article  CAS  Google Scholar 

  18. Jack, C.R. Jr. & Holtzman, D.M.B. Neuron 80, 1347–1358 (2013).

    Article  CAS  Google Scholar 

  19. Jansen, W.J. et al. J. Am. Med. Assoc. 313, 1924–1938 (2015).

    Article  Google Scholar 

  20. Thal, D.R., Rub, U., Orantes, M. & Braak, H. Neurology 58, 1791–1800 (2002).

    Article  Google Scholar 

  21. Calhoun, M.E. et al. Proc. Natl. Acad. Sci. USA 96, 14088–14093 (1999).

    Article  CAS  Google Scholar 

  22. Eisele, Y.S. et al. J. Neurosci. 34, 10264–10273 (2014).

    Article  Google Scholar 

  23. Maia, L.F. et al. Sci. Transl. Med. 5, 194re192 (2013).

    Article  Google Scholar 

Download references


We would like to thank L. Goepfert and T. Joos (NMI, Reutlingen) and M. Hruscha, M. Lambert and L. Haesler for help with the immunoassays, A. Bosch, C. Krüger, J. Odenthal and all of the other members of our department for experimental help, and C. Haass (Munich) for antibody donation. This work was supported by grants from the Competence Network on Degenerative Dementias (BMBF-01GI0705) and the EC Joint Programme on Neurodegenerative Diseases (JPND-NeuTARGETs). L.Y. was supported by a Chinese Scholarship Council grant for PhD scholarship.

Author information

Authors and Affiliations



L.Y., S.K.F., J.S. and U.O. performed the experimental work. L.Y., S.K.F., J.S., U.O., K.D., S.A.K., F.B. and M.J. carried out the analysis. Experimental design and preparation of the manuscript was done by L.Y., S.K.F., Y.S.E., L.C.W., M.S. and M.J.

Corresponding author

Correspondence to Mathias Jucker.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Ultra-sensitive bead-based Simoa technology detects residual human Aβ in hippocampal extracts of inoculated App−/− mice.

Aβ seed-containing APP23 brain extract or seed-negative WT mouse brain extract was injected into the hippocampus of App−/− mice. The injected hippocampi were isolated 1, 30, 60, or 180 dpi (see Figures 1 and 2). While ECL-linked immunoassay no longer detected any Aβ at and beyond 30 dpi (Figure 1), the bead-based Simoa technology detected human Aβ up to 180 dpi. Note that the majority of Aβ was cleared within the first 30d with much slower clearance of residual Aβ thereafter. (The same samples were analysed as in Figures 1 and 2, thus n = 6, 10, 5, and 5 for 1d, 30d, 60d, and 180d, respectively). One-way ANOVA for the APP transgenic extracts revealed F(3,22) = 8.932, P = 0.0007. Bonferroni post hoc test for pairwise comparisons, **P<0.01, ***P<0.001. WT-injected mice (n = 4; 30 or 60 dpi).

Supplementary Figure 2 Induced amyloid lesions are partly congophilic and surrounded by activated microglia and dystrophic boutons.

(a) Congo red-positive amyloid deposits induced in the dentate gyrus were surrounded by Iba1-positive microglia (black). (b) Congo red-positive plaque with surrounding hypertrophic microglial cell bodies and processes at higher magnification. (c) APP-immunoreactive dystrophic processes and boutons (black) in close proximity to a congophilic amyloid plaque. Images are from a 1 or 30 dpi App−/− hippocampal extract-inoculated APP23 mouse. Scale bar: 100 μm (a), 20 μm (b,c).

Supplementary Figure 3 Cerebral amyloid angiopathy (CAA) was always induced in addition to parenchymal amyloid.

(a) Shown are the Aβ-immunostained and Congo red-stained hippocampus and thalamus of an APP23 mouse that had been inoculated with a 30 dpi App−/− hippocampal extract 8 months earlier. Note the prominent CAA in the thalamus (asterisk). Scale bar: 200 μm. (b) Perl´s Prussian blue staining of an adjacent section reveals multiple microhemorrhages in the CAA-laden thalamic region (arrow). Insert shows the microhemorrhages at higher magnification. Scale bars: 200 μm and (inset) 50 μm.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ye, L., Fritschi, S., Schelle, J. et al. Persistence of Aβ seeds in APP null mouse brain. Nat Neurosci 18, 1559–1561 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing