Regulation of Amyloid β oligomer binding to neurons and neurotoxicity by the complex prion protein/mGluR5.

Abstract

The prion protein (PrPC) has been suggested to operate as a scaffold/ receptor protein in neurons, participating in both physiological and pathological associated events. PrPC, laminin, and metabotropic glutamate receptor 5 (mGluR5) form a protein complex on the plasma membrane that can trigger signaling pathways involved in neuronal differentiation. PrPC and mGluR5 are co-receptors also for -amyloid oligomers(A Os)andhavebeenshowntomodulate toxicity and neuronal death in Alzheimer’s disease. In the present work, we addressed the potential crosstalk between these two signaling pathways, laminin-PrPC-mGluR5 or A O-PrPC- mGluR5, as well as their interplay. Herein, we demonstrated that an existing complex containing PrPC-mGluR5 has an important role in A Obinding and activity in neurons. A peptide mimicking the binding site of laminin onto PrPC (Ln- 1) binds to PrPC and induces intracellular Ca2 increase in neurons via the complex PrPC-mGluR5. Ln- 1 promotes internalization of PrPC and mGluR5 and transiently decreases A O biding to neurons; however, the peptide does not impactA Otoxicity.GiventhatmGluR5 is critical for toxic signaling by A Os 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 PrPC-mGluR5 form a functional response unit by which multiple ligands can trigger signaling. We propose that trafficking of PrPC-mGluR5 may modulate signaling intensity by different PrPC ligands.