Dataset Information

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

ABSTRACT: The prion protein (PrP^C) has been suggested to operate as a scaffold/receptor protein in neurons, participating in both physiological and pathological associated events. PrP^C, 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^C 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^C-mGluR5 or AβO-PrP^C-mGluR5, as well as their interplay. Herein, we demonstrated that an existing complex containing PrP^C-mGluR5 has an important role in AβO binding and activity in neurons. A peptide mimicking the binding site of laminin onto PrP^C (Ln-γ1) binds to PrP^C and induces intracellular Ca²⁺ increase in neurons via the complex PrP^C-mGluR5. Ln-γ1 promotes internalization of PrP^C 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^C-mGluR5 form a functional response unit by which multiple ligands can trigger signaling. We propose that trafficking of PrP^C-mGluR5 may modulate signaling intensity by different PrP^C ligands.

SUBMITTER: Beraldo FH

PROVIDER: S-EPMC5063978 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Beraldo Flavio H FH Ostapchenko Valeriy G VG Caetano Fabiana A FA Guimaraes Andre L S AL Ferretti Giulia D S GD Daude Nathalie N Bertram Lisa L Nogueira Katiane O P C KO Silva Jerson L JL Westaway David D Cashman Neil R NR Martins Vilma R VR Prado Vania F VF Prado Marco A M MA

The Journal of biological chemistry 20160825 42

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 β-amyloid oligomers (AβOs) and have been shown to modulate toxicity and n ...[more]

PMID: 27563063

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Project description:Oligomeric species of amyloid β peptide (Aβ) are pivotal in Alzheimer's disease (AD) pathogenesis, making them valuable therapeutic targets. Currently, there is no cure or preventive therapy available for AD, with only a few therapeutics offering temporary alleviation of symptoms. Natural products (NPs) are now considered promising anti-amyloid agents. Green tea catechins have garnered considerable attention due to their ability to remodel the toxic amyloid β peptide oligomers (AβOs) into non-toxic assemblies. Nevertheless, the precise molecular mechanism underlying their effects on AβOs remains unclear. In this study, we employ a combination of binding site prediction, molecular docking, and dynamics simulations to gain mechanistic insights into the binding of the potent anti-amyloid epigallocatechin-3-gallate (EGCG) and the less effective catechin, epicatechin (EC), on the structure of pore-forming Aβ tetramers (PDB ID 6RHY). This recently elucidated structure represents AβO(1-42) with two faces of the hydrophobic β-sheet core and hydrophilic edges. Our simulations revealed three potential druggable binding sites within the AβO: two in hydrophilic edges and one in the β-sheet core. Although both catechins bind via hydrogen bond (H-bond) and aromatic interactions to the three potential binding sites, EGCG interacted with key residues more efficiently than EC. We propose that EGCG may remodel AβOs preventing pore formation by binding to the hydrophilic edge binding sites. Additionally, EGCG interacts with key residues in the oligomer's β-sheet core binding site, crucial for fibrillar aggregation. A better understanding of how anti-amyloid compounds remodelling AβOs could be valuable for the development of new therapeutic strategies targeting Aβ in AD. Further experimental validation using point mutations involving key residues could be useful to define whether the establishment of these interactions is crucial for the EGCG remodelling effect.

Dataset Information

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

Publications

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

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