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Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease

Laura T. Haas, Santiago V. Salazar, Mikhail A. Kostylev, Ji Won Um, Adam C. Kaufman, Stephen M. Strittmatter
DOI: http://dx.doi.org/10.1093/brain/awv356 526-546 First published online: 14 December 2015

Summary

Alzheimer’s disease-related phenotypes in mice can be rescued by blockade of either cellular prion protein or metabotropic glutamate receptor 5. We sought genetic and biochemical evidence that these proteins function cooperatively as an obligate complex in the brain. We show that cellular prion protein associates via transmembrane metabotropic glutamate receptor 5 with the intracellular protein mediators Homer1b/c, calcium/calmodulin-dependent protein kinase II, and the Alzheimer’s disease risk gene product protein tyrosine kinase 2 beta. Coupling of cellular prion protein to these intracellular proteins is modified by soluble amyloid-β oligomers, by mouse brain Alzheimer’s disease transgenes or by human Alzheimer’s disease pathology. Amyloid-β oligomer-triggered phosphorylation of intracellular protein mediators and impairment of synaptic plasticity in vitro requires Prnp–Grm5 genetic interaction, being absent in transheterozygous loss-of-function, but present in either single heterozygote. Importantly, genetic coupling between Prnp and Grm5 is also responsible for signalling, for survival and for synapse loss in Alzheimer’s disease transgenic model mice. Thus, the interaction between metabotropic glutamate receptor 5 and cellular prion protein has a central role in Alzheimer’s disease pathogenesis, and the complex is a potential target for disease-modifying intervention.

  • Alzheimer’s disease
  • amyloid-beta oligomers
  • cellular prion protein
  • metabotropic glutamate receptor 5
  • homer
  • Abbreviations
    APP/PS1+
    amyloid precursor protein/presenilin 1
    CamKII
    calcium/calmodulin-dependent protein kinase II
    eEF2
    eukaryotic elongation factor 2
    EPSP
    excitatory postsynaptic potential
    HEK-293T
    human embryonic kidney-293T
    Homer1a/b/c
    homer scaffolding protein 1 splice variants a/b/c
    LTP
    long-term potentiation
    mGluR5
    metabotropic glutamate receptor 5
    PrPC
    cellular prion protein
    Pyk2
    proline rich tyrosine kinase 2
    RIPA
    radioimmunoprecipitation assay
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