title: Tissue-type plasminogen activator mediates neuroglial coupling in the central nervous system.
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.
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA; Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors.forename: J
authors.initials: J
authors.lastname: An
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: W B
authors.initials: WB
authors.lastname: Haile
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Torre
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology, Veterans Affairs Medical Center, Atlanta, GA, USA. Electronic address: myepes@emory.edu.
authors.forename: M
authors.initials: M
authors.lastname: Yepes
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001089:Arabinose / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology; D050113:Imino Furanoses / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D013402:Sugar Alcohols / Q000494:pharmacology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D051272:Glucose Transporter Type 1; D050113:Imino Furanoses; D013402:Sugar Alcohols; C058137:1,4-dideoxy-1,4-iminoarabinitol; D019344:Lactic Acid; D001089:Arabinose; D055372:AMP-Activated Protein Kinases; D010959:Tissue Plasminogen Activator; D005947:Glucose
keywords: 1,4-dideoxy-1,4-imino-d-arabinitol hydrochloride; 2-N (7-nitrobenz-2-oxa-1,3-diazol-4-yl-amino)-2-deoxyglucose; 2-NBDG; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; 4′-6-diamidino-2-phenylindole; AMPK; BBB; BCA; DAPI; DH; ELISA; GFAP; GLUT1; HEPES; MCT-2; MTT; N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid; OGD; RBMVEC; adenosine monophosphate-activated protein kinase; adenosine monophosphate-activated protein kinase (AMPK); bicinchoninic acid; blood–brain barrier; enzyme-linked immunosorbent assay; glial fibrillary acidic protein; glucose metabolism; glucose transporter-1; monocarboxylate transporter-2; monocarboxylate transporter-2 (MCT-2); neuroprotection; oxygen and glucose deprivation; rat brain microvascular endothelial cells; tPA; tissue-type plasminogen activator; tissue-type plasminogen activator (tPA)