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Cystatin C inhibits amyloid-β deposition in Alzheimer's disease mouse models

Nature Genetics volume 39, pages 1440–1442 (2007)Cite this article

Abstract

Using transgenic mice expressing human cystatin C (encoded by CST3), we show that cystatin C binds soluble amyloid-β peptide and inhibits cerebral amyloid deposition in amyloid-β precursor protein (APP) transgenic mice. Cystatin C expression twice that of the endogenous mouse cystatin C was sufficient to substantially diminish amyloid-β deposition. Thus, cystatin C has a protective role in Alzheimer's disease pathogenesis, and modulation of cystatin C concentrations may have therapeutic implications for the disease.

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Figure 1: APP overexpression diminishes cystatin C (CysC) dimerization.
Figure 2: Cystatin C (CysC) overexpression robustly decreased amyloid-β plaque load in APP and CysC double transgenic mice compared with APP singly transgenic mice.

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Acknowledgements

We acknowledge financial support from the US National Institute of Neurological Disorders and Stroke (NS42029), National Institute on Aging (AG017617) and American Heart Association (0040102N). We thank M. Staufenbiel for APP23 transgenic mice, K. Hsiao Ashe for Tg2576 transgenic mice, and J. Berger and M. Mazzella for technical assistance.

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Author notes

  1. Magdalena Sastre & Sonia S Jung

    Present address: Present addresses: Department of Cellular and Molecular Neuroscience, Imperial College London, London W12 0NN, UK (M.S.) and Centocor Research and Development Inc., Radnor, Pennsylvania 19087, USA (S.S.J.).,

Authors and Affiliations

  1. Nathan S. Kline Institute, Orangeburg, 10962, New York, USA

    Weiqian Mi, Monika Pawlik, Sonia S Jung, David S Radvinsky, Andrew M Klein, John Sommer, Stephen D Schmidt, Ralph A Nixon, Paul M Mathews & Efrat Levy

  2. Department of Pharmacology, New York University School of Medicine, New York, 10016, New York, USA

    Monika Pawlik, Magdalena Sastre & Efrat Levy

  3. Department of Psychiatry, New York University School of Medicine, New York, 10016, New York, USA

    Ralph A Nixon, Paul M Mathews & Efrat Levy

  4. Department of Cell Biology, New York University School of Medicine, New York, 10016, New York, USA

    Ralph A Nixon

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Contributions

W.M., with the help of S.S.J., performed the experimental work with the exception of the histological analyses, which were done by D.S.R., A.M.K. and J.S., and ELISA analysis, which was performed by S.D.S. The crosses between CysC and APP transgenic mice were generated by M.P. with the help of M.S. R.A.N. and P.M.M. assisted in the manuscript preparation and data interpretation. E.L. designed and supervised the study, interpreted findings and finalized the manuscript preparation.

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Correspondence to Efrat Levy.

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Supplementary Methods, Supplementary Figure 1 (PDF 253 kb)

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Mi, W., Pawlik, M., Sastre, M. et al. Cystatin C inhibits amyloid-β deposition in Alzheimer's disease mouse models. Nat Genet 39, 1440–1442 (2007). https://doi.org/10.1038/ng.2007.29

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