Regulation of Amyloid β Oligomer Binding to Neurons and Neurotoxicity by the Prion Protein-mGluR5 Complex.

The prion protein (PrP) has been suggested to operate as a scaffold/receptor protein in neurons, participating in both physiological and pathological associated events. PrP, laminin, and metabotropic glutamate receptor 5 (mGluR5) form a protein complex on the plasma membrane that can trigger signaling pathways involved in neuronal differentiation. PrP and mGluR5 are co-receptors also for β-amyloid oligomers (AβOs) and have been shown to modulate toxicity and neuronal death in Alzheimer's disease. In the present work, we addressed the potential crosstalk between these two signaling pathways, laminin-PrP-mGluR5 or AβO-PrP-mGluR5, as well as their interplay. Herein, we demonstrated that an existing complex containing PrP-mGluR5 has an important role in AβO binding and activity in neurons. A peptide mimicking the binding site of laminin onto PrP (Ln-γ1) binds to PrP and induces intracellular Ca increase in neurons via the complex PrP-mGluR5. Ln-γ1 promotes internalization of PrP and mGluR5 and transiently decreases AβO biding to neurons; however, the peptide does not impact AβO toxicity. Given that mGluR5 is critical for toxic signaling by AβOs and in prion diseases, we tested whether mGlur5 knock-out mice would be susceptible to prion infection. Our results show mild, but significant, effects on disease progression, without affecting survival of mice after infection. These results suggest that PrP-mGluR5 form a functional response unit by which multiple ligands can trigger signaling. We propose that trafficking of PrP-mGluR5 may modulate signaling intensity by different PrP ligands.