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Therapeutic molecules and endogenous ligands regulate the interaction between brain cellular prion protein (PrPC) and

Laura T Haas1, Mikhail A Kostylev2, Stephen M Strittmatter3

  • 1From the Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06536 and the Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, D-72074 Tübingen, Germany.

The Journal of Biological Chemistry
|August 23, 2014
PubMed

Insights

Soluble amyloid-beta oligomers trigger Alzheimer

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Soluble amyloid-beta oligomers (Aβo) initiate Alzheimer disease (AD) pathophysiology.
  • Cellular prion protein (PrP(C)) binds Aβo and interacts with metabotropic glutamate receptor 5 (mGluR5).
  • This PrP(C)-mGluR5 interaction transmits neurotoxic signals, presenting a therapeutic target for AD.

Purpose of the Study:

  • To develop assays for studying the PrP(C)-mGluR5 interaction.
  • To investigate the effects of ligands, agonists, antagonists, and antibodies on this interaction.
  • To identify potential therapeutic strategies for inhibiting PrP(C)-mGluR5 signaling in AD.

Main Methods:

  • Utilized cell lines and mouse brain models.
  • Developed assays to measure PrP(C)-mGluR5 interaction.
  • Tested endogenous ligands, agonists, antagonists, antibodies, and silent allosteric modulators.

Main Results:

  • The PrP(C) segment (amino acids 91-153) mediates mGluR5 interaction.
  • mGluR5 agonists enhance, while antagonists suppress, the interaction.
  • Aβo promotes PrP(C)-mGluR5 interaction, significantly increased in AD models; this can be reversed by antagonists or anti-PrP(C) antibodies.
  • Silent allosteric mGluR5 modulators disrupt Aβo-induced PrP(C)-mGluR5 interaction without affecting basal activity.

Conclusions:

  • The PrP(C)-mGluR5 interaction is a key pathway for Aβo-induced neurotoxicity in Alzheimer disease.
  • mGluR5 antagonists and specific antibodies targeting PrP(C) can reverse this interaction.
  • Silent allosteric modulators offer a novel therapeutic approach by disrupting the pathogenic signaling cascade.
Keywords:
Alzheimer DiseaseAmyloid-β (AB)Metabotropic Glutamate Receptor (mGluR)Neurodegenerative DiseasePrionProtein-Protein InteractionTherapeutic Modulation

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