title: Peptide-binding GRP78 protects neurons from hypoxia-induced apoptosis.
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.
authors: Eye Research Laboratory, Felsenstein Medical Research Center, Tel-Aviv University, School of Medicine, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
authors: Nitza
authors: N
authors: Goldenberg-Cohen
authors: Annat
authors: A
authors: Raiter
authors: Vera
authors: V
authors: Gaydar
authors: Olga
authors: O
authors: Dratviman-Storobinsky
authors: Tamar
authors: T
authors: Goldstein
authors: Abraham
authors: A
authors: Weizman
authors: Britta
authors: B
authors: Hardy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001253:Astrocytes / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D009900:Optic Nerve / Q000098:blood supply; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: C572757:ADAM15 protein (286-297); D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D009842:Oligopeptides; D045304:Cytochromes c