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Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein

Ji Won Um1, Adam C Kaufman, Mikhail Kostylev

  • 1Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT 06536, USA.

Neuron
|September 10, 2013
PubMed

Insights

Soluble amyloid-beta oligomers (Aβo) bind cellular prion protein (PrP(C)) and activate Fyn kinase via mGluR5, disrupting synapses in Alzheimer

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Soluble amyloid-beta oligomers (Aβo) are key drivers of Alzheimer's disease (AD) pathophysiology.
  • Aβo bind cellular prion protein (PrP(C)) with high affinity, initiating downstream signaling at the postsynaptic density (PSD).
  • This interaction activates Fyn kinase, leading to synaptic dysfunction.

Purpose of the Study:

  • To identify transmembrane PSD proteins that couple Aβo-PrP(C) complexes to Fyn kinase.
  • To elucidate the role of mGluR5 in mediating Aβo-induced synaptic disruption in Alzheimer's disease.

Main Methods:

  • Heterologous screening of transmembrane PSD proteins for coupling Aβo-PrP(C) with Fyn kinase.
  • Co-immunoprecipitation to assess protein interactions (PrP(C)-mGluR5, Fyn-mGluR5).
  • Calcium imaging in Xenopus oocytes and primary neurons to measure intracellular calcium changes.
  • Assessment of eEF2 phosphorylation and dendritic spine density.
  • Behavioral testing and synaptic density analysis in transgenic mouse models of AD.

Main Results:

  • Metabotropic glutamate receptor 5 (mGluR5) coexpression enabled Aβo-PrP(C) to activate Fyn kinase.
  • Physical interaction confirmed between PrP(C) and mGluR5, with Fyn forming a complex with mGluR5.
  • Aβo-PrP(C) triggered mGluR5-mediated calcium increases in oocytes and neurons, also observed with human AD brain extracts.
  • Signaling through Aβo-PrP(C)-mGluR5 complexes led to eEF2 phosphorylation and dendritic spine loss.
  • mGluR5 antagonism reversed cognitive and synaptic deficits in AD mouse models.

Conclusions:

  • Aβo-PrP(C) complexes activate neuronal mGluR5, mediating downstream signaling that disrupts synaptic function and contributes to Alzheimer's disease.
  • mGluR5 is a critical mediator linking Aβo-PrP(C) binding to Fyn kinase activation and subsequent neurotoxicity.
  • Targeting the Aβo-PrP(C)-mGluR5 interaction represents a potential therapeutic strategy for Alzheimer's disease.

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