Cited by 581Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Um, Ji Won, Kaufman, Adam C., Kostylev, Mikhail, Heiss, Jacqueline K., Stagi, Massimiliano, Takahashi, Hideyuki, Kerrisk, Meghan E., Vortmeyer, Alexander +5 more·2013·Neuron

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.

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Crossref · 10.1016/j.neuron.2013.06.036

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  • Aβ oligomers can drive additional vicious cycles by stimulating metabotropic glutamate receptor 5 (mGluR5), which activates feedforward Ca2+-cAMP signaling and drives tau phosphorylation.

    “Aβ oligomers can drive additional vicious cycles by stimulating metabotropic glutamate receptor 5 (mGluR5)146,147, which activates feedforward Ca2+–cAMP signaling and drive tau phosphorylation (Fig. 5, brown).”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [147]

    The Results section (‘Aβo Signals through PrPC and mGluR5 to Protein Translation Machinery’; page unavailable) reports that Aβ oligomers signal through mGluR5 to alter calcium levels and phosphorylate eEF2. The Discussion (‘Signaling downstream of mGluR5’; page unavailable) describes calcium signaling and only a possible implication involving tau; it does not establish feedforward Ca2+–cAMP signaling or tau phosphorylation. (LLM, conf=0.88)

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Authors
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.
Affiliations
Yale University (US)
Corresponding author
Strittmatter, Stephen M.
Venue
Neuron
Publisher
Elsevier BV
Published
2013-09
Volume
79
Issue
5
Pages
887-902
ISSN
0896-6273 (ISSN-L)
OpenAlex
W2061342941
Cited by
572
References
65
Citations by year
2026: 28 · 2025: 31 · 2024: 29 · 2023: 35 · 2022: 38 · 2021: 32 · 2020: 59 · 2019: 45 · 2018: 46 · 2017: 63 · 2016: 59 · 2015: 58 · 2014: 45 · 2013: 4
FWCI
34.36
Type
journal article
Language
en
Update notices
erratum (2013-10-16)
Open access
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institute on Aging (P30AG008051, R01AG034924)
  • National Institute of General Medical Sciences (T32GM007223, T32GM007205)
  • National Institute of Neurological Disorders and Stroke (R01NS074319, R01NS073502, R01NS080388)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
metabotropic glutamate receptor 5, amyloid-beta oligomers, cellular prion protein, Alzheimer's disease, Fyn, postsynaptic density, intracellular calcium signaling, eEF2 phosphorylation, dendritic spine loss, learning and memory impairment, synaptic loss
MeSH terms
Alzheimer Disease, Animals, Calcium, Cells, Cultured, Humans, Neurons, Oocytes, Phosphorylation, Xenopus, Signal Transduction, Amyloid beta-Peptides, Receptors, Metabotropic Glutamate, PrPC Proteins, Proto-Oncogene Proteins c-fyn, Mice, Elongation Factor 2 Kinase, HEK293 Cells, Post-Synaptic Density, Receptor, Metabotropic Glutamate 5

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