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Cystatin C modulates cerebral β-amyloidosis


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.

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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.


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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).

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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.

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Correspondence to Mathias Jucker.

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

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Kaeser, S., Herzig, M., Coomaraswamy, J. et al. Cystatin C modulates cerebral β-amyloidosis. Nat Genet 39, 1437–1439 (2007).

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