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

doi:10.1016/j.neuron.2013.06.036

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

Department of Brain Sciences

Research output: Contribution to journal › Article › peer-review

500 Scopus citations

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

Original language	English
Pages (from-to)	887-902
Number of pages	16
Journal	Neuron
Volume	79
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2013.06.036
State	Published - 4 Sep 2013

Bibliographical note

Funding Information:
We thank Yiguang Fu and Stefano Sodi for excellent technical support. We thank Xinran Liu of the Yale Center for Cell Imaging for advice on synapse ultrastructure analysis. S.M.S. is a cofounder of Axerion Therapeutics, seeking to develop NgR- and PrP-based therapeutics. H.B.N. is an Ellison Medical Foundation AFAR Postdoctoral Fellow and S.M.S. is a member of the Kavli Institute for Neuroscience at Yale University. We acknowledge support from the National Institutes of Health to S.M.S., A.J.K., and T.W., and from the Falk Medical Research Trust and the Alzheimer’s Association to S.M.S.

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10.1016/j.neuron.2013.06.036

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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

@article{ab86d86a95ff44f89a0d145e34d126c5,

title = "Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein",

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",

author = "Um, \{Ji Won\} and Kaufman, \{Adam C.\} and Mikhail Kostylev and Heiss, \{Jacqueline K.\} and Massimiliano Stagi and Hideyuki Takahashi and Kerrisk, \{Meghan E.\} and Alexander Vortmeyer and Thomas Wisniewski and Koleske, \{Anthony J.\} and Gunther, \{Erik C.\} and Nygaard, \{Haakon B.\} and Strittmatter, \{Stephen M.\}",

note = "Funding Information: We thank Yiguang Fu and Stefano Sodi for excellent technical support. We thank Xinran Liu of the Yale Center for Cell Imaging for advice on synapse ultrastructure analysis. S.M.S. is a cofounder of Axerion Therapeutics, seeking to develop NgR- and PrP-based therapeutics. H.B.N. is an Ellison Medical Foundation AFAR Postdoctoral Fellow and S.M.S. is a member of the Kavli Institute for Neuroscience at Yale University. We acknowledge support from the National Institutes of Health to S.M.S., A.J.K., and T.W., and from the Falk Medical Research Trust and the Alzheimer{\textquoteright}s Association to S.M.S. ",

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doi = "10.1016/j.neuron.2013.06.036",

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AU - Um, Ji Won

AU - Kaufman, Adam C.

AU - Kostylev, Mikhail

AU - Heiss, Jacqueline K.

AU - Stagi, Massimiliano

AU - Takahashi, Hideyuki

AU - Kerrisk, Meghan E.

AU - Vortmeyer, Alexander

AU - Wisniewski, Thomas

AU - Koleske, Anthony J.

AU - Gunther, Erik C.

AU - Nygaard, Haakon B.

AU - Strittmatter, Stephen M.

N1 - Funding Information: We thank Yiguang Fu and Stefano Sodi for excellent technical support. We thank Xinran Liu of the Yale Center for Cell Imaging for advice on synapse ultrastructure analysis. S.M.S. is a cofounder of Axerion Therapeutics, seeking to develop NgR- and PrP-based therapeutics. H.B.N. is an Ellison Medical Foundation AFAR Postdoctoral Fellow and S.M.S. is a member of the Kavli Institute for Neuroscience at Yale University. We acknowledge support from the National Institutes of Health to S.M.S., A.J.K., and T.W., and from the Falk Medical Research Trust and the Alzheimer’s Association to S.M.S.

PY - 2013/9/4

Y1 - 2013/9/4

N2 - 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

AB - 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

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DO - 10.1016/j.neuron.2013.06.036

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SN - 0896-6273

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SP - 887

EP - 902

JO - Neuron

JF - Neuron

IS - 5

ER -

Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein

Abstract

Bibliographical note

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