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Neuron. 2013 Sep 4;79(5):887-902. doi: 10.1016/j.neuron.2013.06.036.

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

Author information

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

Erratum in

  • Neuron. 2013 Oct 16;80(2):531.

Abstract

Soluble amyloid-β oligomers (Aβo) trigger Alzheimer's disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrP(C)). At the postsynaptic density (PSD), extracellular Aβo bound to lipid-anchored PrP(C) activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo-PrP(C) with Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrP(C)-bound Aβo to activate Fyn. PrP(C) and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Aβo-PrP(C) generates mGluR5-mediated increases of intracellular calcium in Xenopus oocytes and in neurons, and the latter is also driven by human AD brain extracts. In addition, signaling by Aβo-PrP(C)-mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory, and synapse density. Thus, Aβo-PrP(C) complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.

PMID:
24012003
PMCID:
PMC3768018
DOI:
10.1016/j.neuron.2013.06.036
[Indexed for MEDLINE]
Free PMC Article

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