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

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2013 Sep 10

PMID 24012003

Citations 308

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Genetic and pharmacologic enhancement of SUMO2 conjugation prevents and reverses cognitive impairment and synaptotoxicity in a preclinical model of Alzheimer's disease.

Fioriti L, Wijesekara N, Argyrousi E, Matsuzaki S, Takamura H, Satoh K Alzheimers Dement. 2025; 21(3):e70030.

PMID: 40047257 PMC: 11883658. DOI: 10.1002/alz.70030.

Tau pathology is associated with postsynaptic metabotropic glutamate receptor 5 (mGluR5) in early Alzheimer's disease in a sex-specific manner.

Wang Y, Wang J, Chen X, Lin Z, You Z, He K Alzheimers Dement. 2025; 21(2):e70004.

PMID: 39998900 PMC: 11853735. DOI: 10.1002/alz.70004.

Unveiling the Interplay: Neurovascular Coupling, Astrocytes and G Protein-Coupled Receptors in Alzheimer's Disease.

Al-Jaf S, Soliman A, El-Yazbi A, Abd-Elrahman K ACS Pharmacol Transl Sci. 2025; 8(2):271-285.

PMID: 39974631 PMC: 11833731. DOI: 10.1021/acsptsci.4c00614.

AMPA receptor diffusional trapping machinery as an early therapeutic target in neurodegenerative and neuropsychiatric disorders.

Choquet D, Opazo P, Zhang H Transl Neurodegener. 2025; 14(1):8.

PMID: 39934896 PMC: 11817889. DOI: 10.1186/s40035-025-00470-z.

eEF2K regulates pain through translational control of BDNF.

Smith P, Garcia G, Meyer A, Ryazanov A, Ma T, Loerch S Mol Cell. 2024; 85(4):756-769.e5.

PMID: 39694034 PMC: 11845307. DOI: 10.1016/j.molcel.2024.11.023.

References

Ronesi J, Collins K, Hays S, Tsai N, Guo W, Birnbaum S . Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci. 2012; 15(3):431-40, S1. PMC: 3288402. DOI: 10.1038/nn.3033. View

Nicolle M, Colombo P, Gallagher M, McKinney M . Metabotropic glutamate receptor-mediated hippocampal phosphoinositide turnover is blunted in spatial learning-impaired aged rats. J Neurosci. 1999; 19(21):9604-10. PMC: 6782926. View

Jankowsky J, Xu G, Fromholt D, Gonzales V, Borchelt D . Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease. J Neuropathol Exp Neurol. 2003; 62(12):1220-7. DOI: 10.1093/jnen/62.12.1220. View

Freir D, Nicoll A, Klyubin I, Panico S, Mc Donald J, Risse E . Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites. Nat Commun. 2011; 2:336. PMC: 3156817. DOI: 10.1038/ncomms1341. View

Bai Y, Markham K, Chen F, Weerasekera R, Watts J, Horne P . The in vivo brain interactome of the amyloid precursor protein. Mol Cell Proteomics. 2007; 7(1):15-34. DOI: 10.1074/mcp.M700077-MCP200. View

Um J, Strittmatter S . Amyloid-β induced signaling by cellular prion protein and Fyn kinase in Alzheimer disease. Prion. 2012; 7(1):37-41. PMC: 3609048. DOI: 10.4161/pri.22212. View

Strittmatter S, Cannon S, Ross E, Higashijima T, Fishman M . GAP-43 augments G protein-coupled receptor transduction in Xenopus laevis oocytes. Proc Natl Acad Sci U S A. 1993; 90(11):5327-31. PMC: 46709. DOI: 10.1073/pnas.90.11.5327. View

Wang Q, Walsh D, Rowan M, Selkoe D, Anwyl R . Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as.... J Neurosci. 2004; 24(13):3370-8. PMC: 6730034. DOI: 10.1523/JNEUROSCI.1633-03.2004. View

Choi K, Chung S, Roche K . Differential binding of calmodulin to group I metabotropic glutamate receptors regulates receptor trafficking and signaling. J Neurosci. 2011; 31(16):5921-30. PMC: 3111228. DOI: 10.1523/JNEUROSCI.6253-10.2011. View

10.

Larson M, Sherman M, Amar F, Nuvolone M, Schneider J, Bennett D . The complex PrP(c)-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease. J Neurosci. 2012; 32(47):16857-71a. PMC: 3568961. DOI: 10.1523/JNEUROSCI.1858-12.2012. View

11.

Roberson E, Halabisky B, Yoo J, Yao J, Chin J, Yan F . Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci. 2011; 31(2):700-11. PMC: 3325794. DOI: 10.1523/JNEUROSCI.4152-10.2011. View

12.

Angers S, Moon R . Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009; 10(7):468-77. DOI: 10.1038/nrm2717. View

13.

Nicodemo A, Pampillo M, Ferreira L, Dale L, Cregan T, Ribeiro F . Pyk2 uncouples metabotropic glutamate receptor G protein signaling but facilitates ERK1/2 activation. Mol Brain. 2010; 3:4. PMC: 2829546. DOI: 10.1186/1756-6606-3-4. View

14.

Jonsson T, Atwal J, Steinberg S, Snaedal J, Jonsson P, Bjornsson S . A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012; 488(7409):96-9. DOI: 10.1038/nature11283. View

15.

Renner M, Lacor P, Velasco P, Xu J, Contractor A, Klein W . Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron. 2010; 66(5):739-54. PMC: 3111138. DOI: 10.1016/j.neuron.2010.04.029. View

16.

Sokol D, Maloney B, Long J, Ray B, Lahiri D . Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links. Neurology. 2011; 76(15):1344-52. PMC: 3090060. DOI: 10.1212/WNL.0b013e3182166dc7. View

17.

Albasanz J, Dalfo E, Ferrer I, Martin M . Impaired metabotropic glutamate receptor/phospholipase C signaling pathway in the cerebral cortex in Alzheimer's disease and dementia with Lewy bodies correlates with stage of Alzheimer's-disease-related changes. Neurobiol Dis. 2005; 20(3):685-93. DOI: 10.1016/j.nbd.2005.05.001. View

18.

Hu J, Park J, Park S, Xiao B, Dehoff M, Kim S . Homeostatic scaling requires group I mGluR activation mediated by Homer1a. Neuron. 2010; 68(6):1128-42. PMC: 3013614. DOI: 10.1016/j.neuron.2010.11.008. View

19.

Zou W, Xiao X, Yuan J, Puoti G, Fujioka H, Wang X . Amyloid-beta42 interacts mainly with insoluble prion protein in the Alzheimer brain. J Biol Chem. 2011; 286(17):15095-105. PMC: 3083157. DOI: 10.1074/jbc.M110.199356. View

20.

Holtzman D, Morris J, Goate A . Alzheimer's disease: the challenge of the second century. Sci Transl Med. 2011; 3(77):77sr1. PMC: 3130546. DOI: 10.1126/scitranslmed.3002369. View