Increased prion protein processing and expression of metabotropic glutamate receptor 1 in a mouse model of Alzheimer's disease

Authors

  • Valeriy G. Ostapchenko,

    1. Robarts Research Institute, Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
    Search for more papers by this author
    • These authors contributed equally to this work.
  • Flavio H. Beraldo,

    1. Robarts Research Institute, Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
    Search for more papers by this author
    • These authors contributed equally to this work.
  • Andre L. S. Guimarães,

    1. Robarts Research Institute, Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
    2. Universidade Estadual de Montes Claros, Montes Claros, MG, Brazil
    Search for more papers by this author
  • Sanju Mishra,

    1. Robarts Research Institute, Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
    Search for more papers by this author
  • Monica Guzman,

    1. Robarts Research Institute, Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
    Search for more papers by this author
  • Jue Fan,

    1. Robarts Research Institute, Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
    Search for more papers by this author
  • Vilma R. Martins,

    1. International Research Center, A. C. Camargo Cancer Center and National Institute for Translational Neuroscience, São Paulo, SP, Brazil
    Search for more papers by this author
  • Vania F. Prado,

    Corresponding author
    1. Robarts Research Institute, Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
    2. Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada
    • Address correspondence and reprint requests to Dr Marco A. M. Prado or Dr Vania F. Prado, Robarts Research Institute, University of Western Ontario, 100 Perth Drive, London, ON N6A5K8, Canada. E-mails: mprado@robarts.ca or vprado@robarts.ca

    Search for more papers by this author
  • Marco A. M. Prado

    Corresponding author
    1. Robarts Research Institute, Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
    2. Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada
    • Address correspondence and reprint requests to Dr Marco A. M. Prado or Dr Vania F. Prado, Robarts Research Institute, University of Western Ontario, 100 Perth Drive, London, ON N6A5K8, Canada. E-mails: mprado@robarts.ca or vprado@robarts.ca

    Search for more papers by this author

Abstract

Prion protein (PrPC), a glycosylphosphatidylinositol-anchored protein corrupted in prion diseases, has been shown recently to interact with group I metabotropic glutamate receptors (mGluRs). Moreover, both PrPC and mGluRs were proposed to function as putative receptors for β-amyloid in Alzheimer's disease. PrPC can be processed in neurons via α or β-cleavage to produce PrPC fragments that are neuroprotective or toxic, respectively. We found PrPC α-cleavage to be 2–3 times higher in the cortex of APPswe/PS1dE9 mice, a mouse model of Alzheimer's disease. A similar age-dependent increase was observed for PrPC β-cleavage. Moreover, we observed considerable age-dependent increase in cortical expression of mGluR1, but not mGluR5. Exposure of cortical neuronal cultures to β-amyloid oligomers upregulated mGluR1 and PrPC α-cleavage, while activation of group I mGluRs increased PrPC shedding from the membrane, likely due to increased levels of a disintegrin and metalloprotease10, a key disintegrin for PrPC shedding. Interestingly, a similar increase in a disintegrin and metalloprotease10 was detected in the cortex of 9-month-old APPswe/PS1dE9 animals. Our experiments reveal novel and complex processing of PrPC in connection with mGluR overexpression that seems to be triggered by β-amyloid peptides.

image

Prion protein (PrPC) and metabotropic glutamate receptors (mGluR) are implicated in Alzheimer's disease (AD). We found age-dependent increase in PrPC processing, ADAM10 and mGluR1 levels in AD mouse model. These changes could be reproduced in cultured cortical neurons treated with Aβ peptide. Our findings suggest that increased levels of Aβ can trigger compensatory responses that may affect neuronal toxicity.

Ancillary