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.
XB-ART-47921
Neuron September 4, 2013; 79 (5): 887-902.
Show Gene links Show Anatomy links

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 .


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.

PubMed ID: 24012003
PMC ID: PMC3768018
Article link: Neuron
Grant support: [+]

Species referenced: Xenopus
Genes referenced: fyn prnp psd

References [+] :
Abu-Elneel, A delta-catenin signaling pathway leading to dendritic protrusions. 2008, Pubmed