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

 Ji Won Um  ;  Adam C. Kaufman  ;  Mikhail Kostylev  ;  Jacqueline K. Heiss  ;  Massimiliano Stagi  ;  Hideyuki Takahashi  ;  Meghan E. Kerrisk  ;  Alexander Vortmeyer  ;  , Thomas Wisniewski  ;  Anthony J. Koleske  ;  Erik C. Gunther  ;  Haakon B. Nygaard  ;  Stephen M. Strittmatter 
 NEURON, Vol.79(5) : 887-902, 2013 
Journal Title
Issue Date
Alzheimer Disease/metabolism* ; Alzheimer Disease/physiopathology ; Amyloid beta-Peptides/metabolism* ; Animals ; Calcium/metabolism ; Cells, Cultured ; Elongation Factor 2 Kinase/metabolism ; HEK293 Cells ; Humans ; Mice ; Neurons/metabolism* ; Oocytes ; Phosphorylation ; Post-Synaptic Density/metabolism ; PrPC Proteins/metabolism* ; Proto-Oncogene Proteins c-fyn/metabolism* ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate/physiology* ; Signal Transduction/physiology* ; Xenopus
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.
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1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Um, Ji Won(엄지원)
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