Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein.
Um JW
,
Kaufman AC
,
Kostylev M
,
Heiss JK
,
Stagi M
,
Takahashi H
,
Kerrisk ME
,
Vortmeyer A
,
Wisniewski T
,
Koleske AJ
,
Gunther EC
,
Nygaard HB
,
Strittmatter SM
.
???displayArticle.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.
Abu-Elneel,
A delta-catenin signaling pathway leading to dendritic protrusions.
2008, Pubmed
Abu-Elneel,
A delta-catenin signaling pathway leading to dendritic protrusions.
2008,
Pubmed
Albasanz,
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.
2005,
Pubmed
An,
Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease.
2003,
Pubmed
Angers,
Proximal events in Wnt signal transduction.
2009,
Pubmed
Bai,
The in vivo brain interactome of the amyloid precursor protein.
2008,
Pubmed
Barry,
Alzheimer's disease brain-derived amyloid-β-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein.
2011,
Pubmed
Bizat,
Neuron dysfunction is induced by prion protein with an insertional mutation via a Fyn kinase and reversed by sirtuin activation in Caenorhabditis elegans.
2010,
Pubmed
Breit,
Alternative G protein coupling and biased agonism: new insights into melanocortin-4 receptor signalling.
2011,
Pubmed
Chen,
Interaction between human prion protein and amyloid-beta (Abeta) oligomers: role OF N-terminal residues.
2010,
Pubmed
Choi,
Differential binding of calmodulin to group I metabotropic glutamate receptors regulates receptor trafficking and signaling.
2011,
Pubmed
Chung,
Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an Alzheimer's disease model mouse.
2010,
Pubmed
Cissé,
Reversing EphB2 depletion rescues cognitive functions in Alzheimer model.
2011,
Pubmed
Collins,
Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome.
2006,
Pubmed
Dravid,
Spontaneous synchronized calcium oscillations in neocortical neurons in the presence of physiological [Mg(2+)]: involvement of AMPA/kainate and metabotropic glutamate receptors.
2004,
Pubmed
Emes,
Evolutionary expansion and anatomical specialization of synapse proteome complexity.
2008,
Pubmed
Freir,
Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites.
2011,
Pubmed
Gimbel,
Memory impairment in transgenic Alzheimer mice requires cellular prion protein.
2010,
Pubmed
Grant,
Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice.
1992,
Pubmed
Hay,
GPCR modulation by RAMPs.
2006,
Pubmed
Heidinger,
Metabotropic glutamate receptor 1-induced upregulation of NMDA receptor current: mediation through the Pyk2/Src-family kinase pathway in cortical neurons.
2002,
Pubmed
Holtzman,
Alzheimer's disease: the challenge of the second century.
2011,
Pubmed
Hu,
Homeostatic scaling requires group I mGluR activation mediated by Homer1a.
2010,
Pubmed
Ittner,
Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.
2010,
Pubmed
Jankowsky,
Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease.
2003,
Pubmed
Jonsson,
A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.
2012,
Pubmed
Larson,
The complex PrP(c)-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease.
2012,
Pubmed
Laurén,
Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers.
2009,
Pubmed
Lee,
Phosphorylation of tau by fyn: implications for Alzheimer's disease.
2004,
Pubmed
Lee,
NMDA receptor-independent long-term depression correlates with successful aging in rats.
2005,
Pubmed
Li,
Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain.
2005,
Pubmed
Linhoff,
An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers.
2009,
Pubmed
Lu,
Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP.
1997,
Pubmed
Lujan,
Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus.
1996,
Pubmed
Lüscher,
Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease.
2010,
Pubmed
Majercak,
LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease.
2006,
Pubmed
Málaga-Trillo,
Regulation of embryonic cell adhesion by the prion protein.
2009,
Pubmed
Ménard,
Successful cognitive aging in rats: a role for mGluR5 glutamate receptors, homer 1 proteins and downstream signaling pathways.
2012,
Pubmed
Moult,
Tyrosine phosphatases regulate AMPA receptor trafficking during metabotropic glutamate receptor-mediated long-term depression.
2006,
Pubmed
Nicodemo,
Pyk2 uncouples metabotropic glutamate receptor G protein signaling but facilitates ERK1/2 activation.
2010,
Pubmed
Nicolle,
Metabotropic glutamate receptor-mediated hippocampal phosphoinositide turnover is blunted in spatial learning-impaired aged rats.
1999,
Pubmed
Oddo,
Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction.
2003,
Pubmed
Park,
Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD.
2008,
Pubmed
Prybylowski,
The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2.
2005,
Pubmed
Rammes,
Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of β-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices.
2011,
Pubmed
Renner,
Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5.
2010,
Pubmed
Robbins,
The Hedgehog signal transduction network.
2012,
Pubmed
Roberson,
Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease.
2011,
Pubmed
Ronesi,
Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome.
2012,
Pubmed
Saugstad,
Metabotropic glutamate receptors activate G-protein-coupled inwardly rectifying potassium channels in Xenopus oocytes.
1996,
Pubmed
,
Xenbase
Schmitt-Ulms,
Time-controlled transcardiac perfusion cross-linking for the study of protein interactions in complex tissues.
2004,
Pubmed
Shankar,
Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
2008,
Pubmed
Shinoda,
Persistent synapse loss induced by repetitive LTD in developing rat hippocampal neurons.
2010,
Pubmed
Simonyi,
Metabotropic glutamate receptor subtype 5 antagonism in learning and memory.
2010,
Pubmed
Sokol,
Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links.
2011,
Pubmed
Strittmatter,
GAP-43 augments G protein-coupled receptor transduction in Xenopus laevis oocytes.
1993,
Pubmed
,
Xenbase
Takasu,
Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors.
2002,
Pubmed
Um,
Amyloid-β induced signaling by cellular prion protein and Fyn kinase in Alzheimer disease.
2013,
Pubmed
Um,
Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons.
2012,
Pubmed
Vanderklish,
Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons.
2002,
Pubmed
Wang,
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 well as metabotropic glutamate receptor type 5.
2004,
Pubmed
Wu,
Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation.
2011,
Pubmed
Xu,
mGluR5 has a critical role in inhibitory learning.
2009,
Pubmed
Zou,
Amyloid-beta42 interacts mainly with insoluble prion protein in the Alzheimer brain.
2011,
Pubmed
