mGluR5 couples amyloid-beta oligomer–cellular prion protein to post-synaptic signaling. Schematic illustrating a central role of Fyn in amyloid-beta oligomer (Aβo) signaling. Binding of Aβo to cellular prion protein (PrPC) triggers mGluR5-dependent signaling events. Proteins are clustered in the post-synaptic density (PSD) and alter N-methyl-d-aspartate receptor (NMDA-R) function, calcium and protein translation. Tau plays a role in localizing Fyn and is a Fyn substrate. The net result of aberrant PrPC–mGluR5–Fyn signaling is synaptic malfunction and loss. Aβ, amyloid-beta; APP, amyloid precursor protein; PrP, prion protein.