Soluble Amyloid-β oligomers (Aβo) trigger Alzheimer’s disease (AD) pathophysiology and bind with high affinity to Cellular Prion Protein (PrP C ). At the post-synaptic 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 co-expression 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 later 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.