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

Research output: Contribution to journalArticle

323 Scopus citations

Abstract

Soluble amyloid-β oligomers (Aβo) trigger Alzheimer@s disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrPC). At the postsynaptic density (PSD), extracellular Aβo bound to lipid-anchored PrPC activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo-PrPC with Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrPC-bound Aβo to activate Fyn. PrPC and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Aβo-PrPC 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-PrPC-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-PrPC complexes at the neuronal surface activate mGluR5 to disrupt neuronal function

Original languageEnglish (US)
Pages (from-to)887-902
Number of pages16
JournalNeuron
Volume79
Issue number5
DOIs
StatePublished - Sep 4 2013
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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    Um, J. W., Kaufman, A. C., Kostylev, M., Heiss, J. K., Stagi, M., Takahashi, H., Kerrisk, M. E., Vortmeyer, A., Wisniewski, T., Koleske, A. J., Gunther, E. C., Nygaard, H. B., & Strittmatter, S. M. (2013). Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein. Neuron, 79(5), 887-902. https://doi.org/10.1016/j.neuron.2013.06.036