First Author | Um JW | Year | 2013 |
Journal | Neuron | Volume | 79 |
Issue | 5 | Pages | 887-902 |
PubMed ID | 24012003 | Mgi Jnum | J:201741 |
Mgi Id | MGI:5515653 | Doi | 10.1016/j.neuron.2013.06.036 |
Citation | Um JW, et al. (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer abeta oligomer bound to cellular prion protein. Neuron 79(5):887-902 |
abstractText | Soluble amyloid-beta oligomers (Abetao) trigger Alzheimer's disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrP(C)). At the postsynaptic density (PSD), extracellular Abetao 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 Abetao-PrP(C) with Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrP(C)-bound Abetao to activate Fyn. PrP(C) and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Abetao-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 Abetao-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, Abetao-PrP(C) complexes at the neuronal surface activate mGluR5 to disrupt neuronal function. |