title: Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein.
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.
authors.affiliation: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Um
authors.forename: Adam C
authors.initials: AC
authors.lastname: Kaufman
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kostylev
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Heiss
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Stagi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Kerrisk
authors.forename: Alexander
authors.initials: A
authors.lastname: Vortmeyer
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koleske
authors.forename: Erik C
authors.initials: EC
authors.lastname: Gunther
authors.forename: Haakon B
authors.initials: HB
authors.lastname: Nygaard
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D054736:Elongation Factor 2 Kinase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes; D010766:Phosphorylation; D057907:Post-Synaptic Density / Q000378:metabolism; D018621:PrPC Proteins / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014981:Xenopus
chemical_list: D016229:Amyloid beta-Peptides; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; D018621:PrPC Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D051076:Proto-Oncogene Proteins c-fyn; D054736:Elongation Factor 2 Kinase; D002118:Calcium