Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein
Open accessAbstract
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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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.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 79
- Issue
- 5
- Pages
- 887-902
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3768018
- 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
- bronze
- doi.org
- Licence
- 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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