The DOI matches its Crossref record; 64 of the 65 references it cites were found in a registry or an index.
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)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]
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“Amyloid-β oligomer binding results in aberrant neuronal signaling and the endocytosis of the dysfunctional synapse into the cell [126,127].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [126]
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“Among the Aβ binding candidates, cellular prion protein (PrPc) represents the most studied, either alone or through a complex with mGluR5 [37, 62, 72, 79].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [72]
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“The most studied binding partner is the PrPc, which through a cascade involving a complex with mGluR5 may lead to toxicity independently or via tau [37, 62, 72, 79].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [72]
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“Amyloid-β oligomers bind to a protein complex comprised of cellular prion protein (PrPc) along with other proteins including leukocyte immunoglobulin-like receptor subfamily B2/paired immunoglobulin-like type 2 receptor B (LilrB2), and possibly also Nogo-66 receptor 1 (Nogo-1), low-affinity nerve growth factor (NGF) receptor [125] (Figure 3), and the metabotropic glutamate receptor 5 [126].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [126]
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Cites
1 retracted
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RetractedTriple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
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Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models
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A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline
Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., et al. (2012) · Nature · doi:10.1038/nature11283 · Cited by 1,738
Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers
Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., & Strittmatter, S. M. (2009) · Nature · doi:10.1038/nature07761 · Cited by 1,560
Self-citationAlzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424
Impaired Long-Term Potentiation, Spatial Learning, and Hippocampal Development in fyn Mutant Mice
Grant, S. G. N., O’Dell, T. J., Karl, K. A., Stein, P. L., Soriano, P. M., & Kandel, E. R. (1992) · Science · doi:10.1126/science.1361685 · Cited by 1,160
Proximal events in Wnt signal transduction
Angers, S., & Moon, R. T. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2717 · Cited by 1,135
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Cited by
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Scheltens, P., Blennow, K., Breteler, M. M. B., de Strooper, B., Frisoni, G. B., Salloway, S., & Van der Flier, W. M. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01124-1 · Cited by 3,125
The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease
Sevigny, J., Chiao, P., Bussière, T., Weinreb, P. H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., et al. (2016) · Nature · doi:10.1038/nature19323 · Cited by 3,059
Gross, K. S., Brandner, D. D., Martinez, L. A., Olive, M. F., Meisel, R. L., & Mermelstein, P. G. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162755 · Cited by 1,610
The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease
Spires-Jones, T. L., & Hyman, B. T. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.004 · Cited by 1,201
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
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Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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