Tissue-type plasminogen activator mediates neuroglial coupling in the central nervous system

• Type of Material: Article
• Authors: Jie An, Emory University; Woldeab B. Haile, Emory University; Fang Wu, Emory University; Enrique Torre, Emory University; Manuel Yepes, Emory University
• Language: English
• Date: 2014-01-17
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuroscience.2013.10.060
• Title of Journal or Parent Work: Neuroscience
• ISSN: 0306-4522
• Volume: 257
• Start Page: 41
• End Page: 48
• Grant/Funding Information: This work was supported in part by National Institutes of Health Grants NS-079331 (to MY), NS-062073 (to M.Y) and VA MERIT award BX000474 (to MY).
• Keywords: Glial Fibrillary Acidic Protein; monocarboxylate transporter-2; Neurons; Glucose Transporter Type 1; Glucose; adenosine monophosphate-activated protein kinase; tPA; BCA; Mice; MCT-2; blood–brain barrier; DH; monocarboxylate transporter-2 (MCT-2); Arabinose; GFAP; adenosine monophosphate-activated protein kinase (AMPK); 2-N (7-nitrobenz-2-oxa-1,3-diazol-4-yl-amino)-2-deoxyglucose; 2-NBDG; OGD; MTT; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; glial fibrillary acidic protein; GLUT1; Time Factors; rat brain microvascular endothelial cells; RBMVEC; N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid; Imino Furanoses; Cells, Cultured; Lactic Acid; neuroprotection; BBB; Tissue Plasminogen Activator; Sugar Alcohols; Cell Death; glucose transporter-1; tissue-type plasminogen activator (tPA); DAPI; ELISA; Embryo, Mammalian; Cerebral Cortex; Animals; AMP-Activated Protein Kinases; HEPES; Neuroglia; Animals, Newborn; AMPK; 1,4-dideoxy-1,4-imino-d-arabinitol hydrochloride; oxygen and glucose deprivation; bicinchoninic acid; tissue-type plasminogen activator; Hypoxia; enzyme-linked immunosorbent assay; 4′-6-diamidino-2-phenylindole; glucose metabolism; Dose-Response Relationship, Drug
• Research Categories: Chemistry, Biochemistry; Health Sciences, Immunology; Biology, Neuroscience

Abstract

The interaction between neurons, astrocytes and endothelial cells plays a central role coupling energy supply with changes in neuronal activity. For a long time it was believed that glucose was the only source of energy for neurons. However, a growing body of experimental evidence indicates that lactic acid, generated by aerobic glycolysis in perivascular astrocytes, is also a source of energy for neuronal activity, particularly when the supply of glucose from the intravascular space is interrupted. Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionary conserved kinase that couples cellular activity with energy consumption via induction of the uptake of glucose and activation of the glycolytic pathway. The uptake of glucose by the blood-brain barrier is mediated by glucose transporter-1 (GLUT1), which is abundantly expressed in endothelial cells and astrocytic end-feet processes. Tissue-type plasminogen activator (tPA) is a serine proteinase that is found in endothelial cells, astrocytes and neurons. Genetic overexpression of neuronal tPA or treatment with recombinant tPA protects neurons from the deleterious effects of metabolic stress or excitotoxicity, via a mechanism independent of tPA's ability to cleave plasminogen into plasmin. The work presented here shows that exposure to metabolic stress induces the rapid release of tPA from murine neurons but not from astrocytes. This tPA induces AMPK activation, membrane recruitment of GLUT1, and GLUT1-mediated glucose uptake in astrocytes and endothelial cells. Our data indicate that this is followed by the synthesis and release of lactic acid from astrocytes, and that the uptake of this lactic acid via the monocarboxylate transporter-2 promotes survival in neurons exposed to metabolic stress.