Skip to main content

Thank you for visiting nature.com. 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.

Cystatin C modulates cerebral β-amyloidosis

Abstract

The CST3 Thr25 allele of CST3, which encodes cystatin C, leads to reduced cystatin C secretion and conveys susceptibility to Alzheimer's disease. Here we show that overexpression of human cystatin C in brains of APP-transgenic mice reduces cerebral amyloid-β deposition and that cystatin C binds amyloid-β and inhibits its fibril formation. Our results suggest that cystatin C concentrations modulate cerebral amyloidosis risk and provide an opportunity for genetic risk assessment and therapeutic interventions.

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.

$32.00

All prices are NET prices.

Figure 1: Cys68 transgenic mice were bred with APP23 transgenic mice.
Figure 2: (a) Immunoprecipitation (IP) of brain homogenates of amyloid-predepositing (3-month-old) double transgenic Cys68+APP23+ mice with an antibody against human cystatin C (A0451) followed by a Bis-Tris gel and subsequent detection of human amyloid-β showed co-immunoprecipitation of cystatin C and amyloid-β.

References

  1. Levy, E. et al. Brain Pathol. 16, 60–70 (2006).

    Article  CAS  Google Scholar 

  2. Herzig, M.C. et al. Nat. Neurosci. 7, 954–960 (2004).

    Article  CAS  Google Scholar 

  3. Radde, R. et al. EMBO Rep. 7, 940–946 (2006).

    Article  CAS  Google Scholar 

  4. Selenica, M.L. et al. Scand. J. Clin. Lab. Invest. 67, 179–190 (2007).

    Article  CAS  Google Scholar 

  5. Balbin, M. et al. Biol. Chem. Hoppe Seyler 373, 471–476 (1992).

    Article  CAS  Google Scholar 

  6. Finckh, U. et al. Arch. Neurol. 57, 1579–1583 (2000).

    Article  CAS  Google Scholar 

  7. Cathcart, H.M. et al. Neurology 64, 755–757 (2005).

    Article  CAS  Google Scholar 

  8. Bertram, L. et al. Nat. Genet. 39, 17–23 (2007).

    Article  CAS  Google Scholar 

  9. Benussi, L. et al. Neurobiol. Dis. 13, 15–21 (2003).

    Article  CAS  Google Scholar 

  10. Paraoan, L. et al. Traffic 5, 884–895 (2004).

    Article  CAS  Google Scholar 

  11. Eriksson, P. et al. Arterioscler. Thromb. Vasc. Biol. 24, 551–557 (2004).

    Article  CAS  Google Scholar 

  12. Chuo, L.J. et al. Dement. Geriatr. Cogn. Disord. 23, 251–257 (2007).

    Article  CAS  Google Scholar 

  13. Ghidoni, R. et al. Neurobiol. Aging 28, 371–376 (2007).

    Article  CAS  Google Scholar 

  14. Bjarnadottir, M. et al. Amyloid 8, 1–10 (2001).

    Article  CAS  Google Scholar 

  15. Filler, G. et al. Clin. Biochem. 38, 1–8 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank H. Blöndal (University of Reykjavik, Iceland) and M. Tolnay (University of Basel, Switzerland) for the tissue of individuals with HCHWA-I and Alzheimer's disease, respectively, and L. Mucke (Gladstone Institute, San Francisco, California) for the GFAP promoter. The experimental help of T. Herbert (Institute for Biometry, Tübingen, Germany), M. Mittelbronn (Institute of Neuropathology, Tübingen, Germany), T. Bolmont, Z. Gao, C. Schäfer, J. Odenthal and R. Radde (Hertie Institute, Tübingen, Germany) are gratefully acknowledged. We also thank L. Walker (Emory University, Atlanta, Georgia) and L. Bertram (Massachusetts General Hospital Institute of Neurodegenerative Disease, Charlestown, Massachusetts) for valuable comments on this manuscript. This work was supported by grants to M.J. from BMBF (NGFN2 and 01GU0522-ARREST-AD), EU contract LSHM-CT-2003-503330 (APOPIS), and to A.G. from the Swedish Research Council (05196).

Author information

Authors and Affiliations

Authors

Contributions

S.A.K., with the help of M.C.H., performed the experimental work with the exception of the gel filtration assays, which were done by M.-L.S. and A.G. The cystatin C transgenic mice were generated by J.C and D.T.W. with the help of E.K. and M.S. The APP23 and CysC knockout mice were provided by M.S. and A.G., respectively. A.G. provided the recombinant cystatin C. E.L. was key to the initiation of this study and provided the cystatin C constructs. M.J. designed and supervised the study. The manuscript was finalized by M.J. with the assistance of all coauthors.

Corresponding author

Correspondence to Mathias Jucker.

Supplementary information

Supplementary Text and Figures

Supplementary Table 1, Supplementary Figures 1–5, Supplementary Methods (PDF 4026 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kaeser, S., Herzig, M., Coomaraswamy, J. et al. Cystatin C modulates cerebral β-amyloidosis. Nat Genet 39, 1437–1439 (2007). https://doi.org/10.1038/ng.2007.23

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2007.23

This article is cited by

Search

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