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Peptide-binding GRP78 protects neurons from hypoxia-induced apoptosis

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Abstract

Brain ischemia has major consequences leading to the apoptosis of astrocytes and neurons. Glucose-regulated protein 78 (GRP78) known for its role in endoplasmic reticulum stress alleviation was discovered on several cell surfaces acting as a receptor for signaling pathways. We have previously described peptides that bind cell surface GRP78 on endothelial cells to induce angiogenesis. We have also reported that ADoPep1 binds cardiomyocytes to prevent apoptosis of ischemic heart cells. In this study we describe the effect of hypoxia on astrocytes and neurons cell surface GRP78. Under hypoxic conditions, there was an increase of more than fivefold in GRP78 on cell surface of neurons while astrocytes were not affected. The addition of the GRP78 binding peptide, ADoPep1, to neurons decreased the percentage of GRP78 positive cells and did not change the percent of astrocytes. However, a significant increase in early and late apoptosis of both astrocytes and neurons under hypoxia was attenuated in the presence of ADoPep1. Intravitreal administration of ADoPep1 to mice in a model of optic nerve crush significantly reduced retinal cell loss after 21 days compared to the crush-damaged eyes without treatment or by control saline vehicle injection. Histological staining demonstrated reduced GRP78 after ADoPep1 treatment. The mechanism of peptide neuroprotection was demonstrated by the inhibition of hypoxia induced caspase 3/7 activity, cytochrome c release and p38 phosphorylation. This study is the first report on hypoxic neuronal and astrocyte cell surface GRP78 and suggests a potential therapeutic target for neuroprotection.

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Acknowledgments

The authors wish to thank Mrs. Sara Dominitz for her editorial assistance.

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Authors and Affiliations

  1. Eye Research Laboratory, Felsenstein Medical Research Center, Tel-Aviv University, School of Medicine, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel

    Nitza Goldenberg-Cohen, Vera Gaydar, Olga Dratviman-Storobinsky & Tamar Goldstein

  2. Department of Ophthalmology Pediatric Unit, Schneider Children’s Medical Center, Petah Tikva, Israel

    Nitza Goldenberg-Cohen, Vera Gaydar, Olga Dratviman-Storobinsky & Tamar Goldstein

  3. The Laboratory of Cellular and Vascular Immunology, Felsenstein Medical Research Center, Tel-Aviv University, School of Medicine, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel

    Annat Raiter & Britta Hardy

  4. The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel

    Vera Gaydar

  5. The Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Tel-Aviv University, School of Medicine, Petah Tikva, Israel

    Abraham Weizman

  6. Geha Mental Health Center, Petah Tikva, Israel

    Abraham Weizman

Authors
  1. Nitza Goldenberg-Cohen
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  2. Annat Raiter
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  3. Vera Gaydar
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  4. Olga Dratviman-Storobinsky
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  5. Tamar Goldstein
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  6. Abraham Weizman
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  7. Britta Hardy
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Corresponding author

Correspondence to Britta Hardy.

Additional information

Nitza Goldenberg-Cohen and Annat Raiter contributed equally to the work.

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Goldenberg-Cohen, N., Raiter, A., Gaydar, V. et al. Peptide-binding GRP78 protects neurons from hypoxia-induced apoptosis. Apoptosis 17, 278–288 (2012). https://doi.org/10.1007/s10495-011-0678-x

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  • DOI: https://doi.org/10.1007/s10495-011-0678-x

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