Metabotropic glutamate receptor 5 – Cellular prion protein complex (mGluR5-PrPC)

The metabotropic glutamate receptor 5 (mGluR5) – cellular prion protein (PrPC) complex is a critical cell-surface signaling unit implicated in the neurodegenerative process of Alzheimer's disease. In this pathological framework, soluble amyloid-beta (Aβ) oligomers bind with high affinity to PrPC, which subsequently recruits and activates mGluR5 as a co-receptor (Um et al., 2013, Neuron). This interaction triggers a toxic signaling cascade involving the activation of Fyn kinase, which leads to the phosphorylation of tau protein and the subsequent loss of dendritic spines and synaptic function (Haas et al., 2017, Nature Communications). Unlike standard glutamatergic transmission, the Aβ-PrPC-mGluR5 axis represents a specific pathological pathway that can be targeted selectively. Therapeutic development focuses on silent allosteric modulators (SAMs), such as BMS-984923, which are designed to block the PrPC-mGluR5 interaction and its downstream neurotoxicity while preserving the receptor's normal response to glutamate (Smith et al., 2020, Science Translational Medicine). This complex is currently a high-priority target for disease-modifying therapies aimed at halting synaptic failure in early-stage Alzheimer's patients.

Other names

mGluR5-PrP complexmGlu5-PrPC complexPrPC-mGluR5 signaling complexAbeta-PrPC-mGluR5 complex

Silent allosteric modulation of mGluR5 to disrupt pathological signaling induced by PrPC-bound amyloid-beta oligomers without affecting normal glutamate signaling.