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Collagen VI protects neurons against Aβ toxicity

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Abstract

Amyloid-β (Aβ) peptides, widely presumed to cause Alzheimer's disease, increased mouse neuronal expression of collagen VI through a mechanism involving transforming growth factor signaling. Reduction of collagen VI augmented Aβ neurotoxicity, whereas treatment of neurons with soluble collagen VI blocked the association of Aβ oligomers with neurons, enhanced Aβ aggregation and prevented neurotoxicity. These results identify collagen VI as an important component of the neuronal injury response and demonstrate its neuroprotective potential.

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Figure 1: Aβ increases neuronal expression of the collagen VI α1 subunit through mechanisms involving TGFβ signaling.
Figure 2: Collagen VI blocks neuronal association and neurotoxicity of Aβ42 oligomers.

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Acknowledgements

We thank H. Solanoy, X. Wang, G.-Q. Yu and Y. Zhou for excellent technical support, S. Maeda for helpful discussions on AFM, P. Scherer for α1(VI)-deficient mice, R. Jaenisch for CamK-Cre93 transgenic mice, H. Moses for TβRIIfl/fl knockin mice, C. Weissmann for APP-deficient mice, M.-L. Chu for the Col6a1 cDNA, the New York Brain Bank at Columbia University Medical Center for human tissues, G. Howard and S. Ordway for editorial review, J. Carroll, T. Roberts and C. Goodfellow for preparation of graphics, and D. McPherson for administrative assistance. Confocal images were acquired at the Nikon Imaging Center at University of California, San Francisco. This work was supported by grants from the US National Institutes of Health, a medical student fellowship from the Howard Hughes Medical Institute, a Larry L. Hillblom Fellowship and a facilities grant from the National Center for Research Resources.

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Author notes

  1. Justin Legleiter & Irene H Cheng

    Present address: Present addresses: Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, USA (J.L.), and National Yang Ming University, Institute of Brain Science, 155 Li-Nong Street, Section 2 Shi-Pai, Taipei, R.O.C. (I.H.C.).,

  2. Jason S Cheng and Dena B Dubal: These authors contributed equally to this work.

Authors and Affiliations

  1. Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, 94158, California, USA

    Jason S Cheng, Dena B Dubal, Daniel H Kim, Justin Legleiter, Irene H Cheng, Gui-Qiu Yu & Lennart Mucke

  2. Department of Neurology, University of California, San Francisco, 1650 Owens Street, San Francisco, 94158, California, USA

    Dena B Dubal, Justin Legleiter, Irene H Cheng & Lennart Mucke

  3. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, 94305, California, USA

    Ina Tesseur & Tony Wyss-Coray

  4. University of Padova, Viale G. Colombo 3, Padova, I-35100, Italy

    Paolo Bonaldo

Authors
  1. Jason S Cheng
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  2. Dena B Dubal
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  4. Justin Legleiter
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  5. Irene H Cheng
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  6. Gui-Qiu Yu
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  7. Ina Tesseur
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  8. Tony Wyss-Coray
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  9. Paolo Bonaldo
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  10. Lennart Mucke
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Contributions

J.S.C. and D.B.D. conducted the experiments and wrote the manuscript. J.L. performed atomic force microscopy analysis. I.H.C. prepared oligomeric Aβ. I.T., T.W.-C. and P.B. provided animal models and helpful discussions. D.H.K. and G.-Q.Y. provided technical assistance. L.M. supervised the project.

Note: Supplementary information is available on the Nature Neuroscience website.

Corresponding author

Correspondence to Lennart Mucke.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Methods (PDF 5183 kb)

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Cheng, J., Dubal, D., Kim, D. et al. Collagen VI protects neurons against Aβ toxicity. Nat Neurosci 12, 119–121 (2009). https://doi.org/10.1038/nn.2240

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