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Different Molecular Mechanisms Mediate Direct or Glia-Dependent Prion Protein Fragment 90–231 Neurotoxic Effects in Cerebellar Granule Neurons

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Abstract

Glia over-stimulation associates with amyloid deposition contributing to the progression of central nervous system neurodegenerative disorders. Here we analyze the molecular mechanisms mediating microglia-dependent neurotoxicity induced by prion protein (PrP)90–231, an amyloidogenic polypeptide corresponding to the protease-resistant portion of the pathological prion protein scrapie (PrPSc). PrP90–231 neurotoxicity is enhanced by the presence of microglia within neuronal culture, and associated to a rapid neuronal [Ca++] i increase. Indeed, while in “pure” cerebellar granule neuron cultures, PrP90–231 causes a delayed intracellular Ca++ entry mediated by the activation of NMDA receptors; when neuron and glia are co-cultured, a transient increase of [Ca++] i occurs within seconds after treatment in both granule neurons and glial cells, then followed by a delayed and sustained [Ca++] i raise, associated with the induction of the expression of inducible nitric oxide synthase and phagocytic NADPH oxidase. [Ca++] i fast increase in neurons is dependent on the activation of multiple pathways since it is not only inhibited by the blockade of voltage-gated channel activity and NMDA receptors but also prevented by the inhibition of nitric oxide and PGE2 release from glial cells. Thus, Ca++ homeostasis alteration, directly induced by PrP90–231 in cerebellar granule cells, requires the activation of NMDA receptors, but is greatly enhanced by soluble molecules released by activated glia. In glia-enriched cerebellar granule cultures, the activation of inducible nitric oxide (iNOS) and NADPH oxidase represents the main mechanism of toxicity since their pharmacological inhibition prevented PrP90–231 neurotoxicity, whereas NMDA blockade by d(−)-2-amino-5-phosphonopentanoic acid is ineffective; conversely, in pure cerebellar granule cultures, NMDA blockade but not iNOS inhibition strongly reduced PrP90–231 neurotoxicity. These data indicate that amyloidogenic peptides induce neurotoxic signals via both direct neuron interaction and glia activation through different mechanisms responsible of calcium homeostasis disruption in neurons and potentiating each other: the activation of excitotoxic pathways via NMDA receptors and the release of radical species that establish an oxidative milieu.

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Acknowledgements

The study was supported by grants from the Italian Ministry of University and Research (Accordi di Programma FIRB 2011, project num. RBAP11HSZS) and Compagnia di San Paolo (2013) to TF and Fondo Ricerca Ateneo (FRA, University of Genova) to ST.

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  1. Stefano Thellung, Elena Gatta, and Francesca Pellistri equally contributed to this study, and all should be considered as first authors.

Authors and Affiliations

  1. Laboratory of Pharmacology, Department of Internal Medicine, and Center of Excellence for Biomedical Research (CEBR), University of Genova, 16132, Genoa, Italy

    Stefano Thellung, Valentina Villa, Alessandro Corsaro, Mario Nizzari & Tullio Florio

  2. Department of Physics, University of Genova, Genoa, Italy

    Elena Gatta, Francesca Pellistri & Mauro Robello

Authors
  1. Stefano Thellung
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  2. Elena Gatta
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  3. Francesca Pellistri
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  4. Valentina Villa
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  5. Alessandro Corsaro
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  6. Mario Nizzari
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  7. Mauro Robello
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  8. Tullio Florio
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Corresponding author

Correspondence to Tullio Florio.

Ethics declarations

Experimental procedures and animal care complied with the EU Parliament and Council Directive of 22 September 2010 (2010/63/EU) and were approved by the Italian Ministry of Health (protocol number 2207-1) in accordance with D.M. 116/1992. All efforts were made to minimize animal suffering and to reduce the number of animal used.

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Thellung, S., Gatta, E., Pellistri, F. et al. Different Molecular Mechanisms Mediate Direct or Glia-Dependent Prion Protein Fragment 90–231 Neurotoxic Effects in Cerebellar Granule Neurons. Neurotox Res 32, 381–397 (2017). https://doi.org/10.1007/s12640-017-9749-2

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  • DOI: https://doi.org/10.1007/s12640-017-9749-2

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