Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact
Identifieur interne : 001222 ( Istex/Corpus ); précédent : 001221; suivant : 001223Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact
Auteurs : Benoit D. Roussel ; Richard Macrez ; Amandine Jullienne ; Véronique Agin ; Eric Maubert ; Luce Dauphinot ; Marie-Claude Potier ; Laurent Plawinski ; Hervé Castel ; Yannick Hommet ; Josep Munuera ; Joan Montaner ; Manuel Yepes ; Carine Ali ; Denis VivienSource :
- Brain [ 0006-8950 ] ; 2009-08.
Abstract
Recombinant tissue-type plasminogen activator (tPA) is the fibrinolytic drug of choice to treat stroke patients. However, a growing body of evidence indicates that besides its beneficial thrombolytic role, tPA can also have a deleterious effect on the ischaemic brain. Although ageing influences stroke incidence, complications and outcome, age-dependent relationships between endogenous tPA and stroke injuries have not been investigated yet. Here, we report that ageing is associated with a selective lowering of brain tPA expression in the murine brain. Moreover, our results show that albumin D site-binding protein (DBP) as a key age-associated regulator of the neuronal transcription of tPA. Additionally, inhibition of DBP-mediated tPA expression confers in vitro neuroprotection. Accordingly, reduced levels of tPA in old mice are associated with smaller excitotoxic/ischaemic injuries and protection of the permeability of the neurovascular unit during cerebral ischaemia. Likewise, we provide neuroradiological evidence indicating the existence of an inverse relationship between age and the volume of the ischaemic lesion in patients with acute ischaemic stroke. Together, these results indicate that the relationship among DBP, tPA and ageing play an important role in the outcome of cerebral ischaemia.
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DOI: 10.1093/brain/awp162
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Roussel</name><affiliation><mods:affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</mods:affiliation></affiliation></author><author><name sortKey="Macrez, Richard" sort="Macrez, Richard" uniqKey="Macrez R" first="Richard" last="Macrez">Richard Macrez</name><affiliation><mods:affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</mods:affiliation></affiliation></author><author><name sortKey="Jullienne, Amandine" sort="Jullienne, Amandine" uniqKey="Jullienne A" first="Amandine" last="Jullienne">Amandine Jullienne</name><affiliation><mods:affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</mods:affiliation></affiliation></author><author><name sortKey="Agin, Veronique" sort="Agin, Veronique" uniqKey="Agin V" first="Véronique" last="Agin">Véronique Agin</name><affiliation><mods:affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</mods:affiliation></affiliation></author><author><name sortKey="Maubert, Eric" sort="Maubert, Eric" uniqKey="Maubert E" first="Eric" last="Maubert">Eric Maubert</name><affiliation><mods:affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</mods:affiliation></affiliation></author><author><name sortKey="Dauphinot, Luce" sort="Dauphinot, Luce" uniqKey="Dauphinot L" first="Luce" last="Dauphinot">Luce Dauphinot</name><affiliation><mods:affiliation>2 Neurobiologie et Diversité Cellulaire, CNRS-UMR 7637, ESPCI, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Potier, Marie Claude" sort="Potier, Marie Claude" uniqKey="Potier M" first="Marie-Claude" last="Potier">Marie-Claude Potier</name><affiliation><mods:affiliation>2 Neurobiologie et Diversité Cellulaire, CNRS-UMR 7637, ESPCI, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Plawinski, Laurent" sort="Plawinski, Laurent" uniqKey="Plawinski L" first="Laurent" last="Plawinski">Laurent Plawinski</name><affiliation><mods:affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</mods:affiliation></affiliation></author><author><name sortKey="Castel, Herve" sort="Castel, Herve" uniqKey="Castel H" first="Hervé" last="Castel">Hervé Castel</name><affiliation><mods:affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</mods:affiliation></affiliation></author><author><name sortKey="Hommet, Yannick" sort="Hommet, Yannick" uniqKey="Hommet Y" first="Yannick" last="Hommet">Yannick Hommet</name><affiliation><mods:affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</mods:affiliation></affiliation></author><author><name sortKey="Munuera, Josep" sort="Munuera, Josep" uniqKey="Munuera J" first="Josep" last="Munuera">Josep Munuera</name><affiliation><mods:affiliation>3 Neuroimaging Unit, Department of Neuroradiology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain</mods:affiliation></affiliation></author><author><name sortKey="Montaner, Joan" sort="Montaner, Joan" uniqKey="Montaner J" first="Joan" last="Montaner">Joan Montaner</name><affiliation><mods:affiliation>4 Neurovascular Research Laboratory, Stroke Unit, Department of Neurology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain</mods:affiliation></affiliation></author><author><name sortKey="Yepes, Manuel" sort="Yepes, Manuel" uniqKey="Yepes M" first="Manuel" last="Yepes">Manuel Yepes</name><affiliation><mods:affiliation>5 Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA30322, USA</mods:affiliation></affiliation></author><author><name sortKey="Ali, Carine" sort="Ali, Carine" uniqKey="Ali C" first="Carine" last="Ali">Carine Ali</name><affiliation><mods:affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ali@cyceron.fr</mods:affiliation></affiliation></author><author><name sortKey="Vivien, Denis" sort="Vivien, Denis" uniqKey="Vivien D" first="Denis" last="Vivien">Denis Vivien</name><affiliation><mods:affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Brain</title><idno type="ISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-08">2009-08</date><biblScope unit="volume">132</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="2219">2219</biblScope><biblScope unit="page" to="2230">2230</biblScope></imprint><idno type="ISSN">0006-8950</idno></series><idno type="istex">BD4E2C9443B938FC3AECA5239FEA6837A5B171A4</idno><idno type="DOI">10.1093/brain/awp162</idno><idno type="ArticleID">awp162</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-8950</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Recombinant tissue-type plasminogen activator (tPA) is the fibrinolytic drug of choice to treat stroke patients. However, a growing body of evidence indicates that besides its beneficial thrombolytic role, tPA can also have a deleterious effect on the ischaemic brain. Although ageing influences stroke incidence, complications and outcome, age-dependent relationships between endogenous tPA and stroke injuries have not been investigated yet. Here, we report that ageing is associated with a selective lowering of brain tPA expression in the murine brain. Moreover, our results show that albumin D site-binding protein (DBP) as a key age-associated regulator of the neuronal transcription of tPA. Additionally, inhibition of DBP-mediated tPA expression confers in vitro neuroprotection. Accordingly, reduced levels of tPA in old mice are associated with smaller excitotoxic/ischaemic injuries and protection of the permeability of the neurovascular unit during cerebral ischaemia. Likewise, we provide neuroradiological evidence indicating the existence of an inverse relationship between age and the volume of the ischaemic lesion in patients with acute ischaemic stroke. Together, these results indicate that the relationship among DBP, tPA and ageing play an important role in the outcome of cerebral ischaemia.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Benoit D. Roussel</name><affiliations><json:string>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</json:string></affiliations></json:item><json:item><name>Richard Macrez</name><affiliations><json:string>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</json:string></affiliations></json:item><json:item><name>Amandine Jullienne</name><affiliations><json:string>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</json:string></affiliations></json:item><json:item><name>Véronique Agin</name><affiliations><json:string>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</json:string></affiliations></json:item><json:item><name>Eric Maubert</name><affiliations><json:string>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</json:string></affiliations></json:item><json:item><name>Luce Dauphinot</name><affiliations><json:string>2 Neurobiologie et Diversité Cellulaire, CNRS-UMR 7637, ESPCI, Paris, France</json:string></affiliations></json:item><json:item><name>Marie-Claude Potier</name><affiliations><json:string>2 Neurobiologie et Diversité Cellulaire, CNRS-UMR 7637, ESPCI, Paris, France</json:string></affiliations></json:item><json:item><name>Laurent Plawinski</name><affiliations><json:string>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</json:string></affiliations></json:item><json:item><name>Hervé Castel</name><affiliations><json:string>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</json:string></affiliations></json:item><json:item><name>Yannick Hommet</name><affiliations><json:string>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</json:string></affiliations></json:item><json:item><name>Josep Munuera</name><affiliations><json:string>3 Neuroimaging Unit, Department of Neuroradiology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain</json:string></affiliations></json:item><json:item><name>Joan Montaner</name><affiliations><json:string>4 Neurovascular Research Laboratory, Stroke Unit, Department of Neurology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain</json:string></affiliations></json:item><json:item><name>Manuel Yepes</name><affiliations><json:string>5 Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA30322, USA</json:string></affiliations></json:item><json:item><name>Carine Ali</name><affiliations><json:string>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</json:string><json:string>E-mail: ali@cyceron.fr</json:string></affiliations></json:item><json:item><name>Denis Vivien</name><affiliations><json:string>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Original Articles</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ageing</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>tissue-type plasminogen activator</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>neurovascular unit</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>albumin D site-binding protein</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>stroke</value></json:item></subject><articleId><json:string>awp162</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Recombinant tissue-type plasminogen activator (tPA) is the fibrinolytic drug of choice to treat stroke patients. However, a growing body of evidence indicates that besides its beneficial thrombolytic role, tPA can also have a deleterious effect on the ischaemic brain. Although ageing influences stroke incidence, complications and outcome, age-dependent relationships between endogenous tPA and stroke injuries have not been investigated yet. Here, we report that ageing is associated with a selective lowering of brain tPA expression in the murine brain. Moreover, our results show that albumin D site-binding protein (DBP) as a key age-associated regulator of the neuronal transcription of tPA. Additionally, inhibition of DBP-mediated tPA expression confers in vitro neuroprotection. Accordingly, reduced levels of tPA in old mice are associated with smaller excitotoxic/ischaemic injuries and protection of the permeability of the neurovascular unit during cerebral ischaemia. Likewise, we provide neuroradiological evidence indicating the existence of an inverse relationship between age and the volume of the ischaemic lesion in patients with acute ischaemic stroke. Together, these results indicate that the relationship among DBP, tPA and ageing play an important role in the outcome of cerebral ischaemia.</abstract><qualityIndicators><score>7.72</score><pdfVersion>1.4</pdfVersion><pdfPageSize>612.68 x 790.866 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>6</keywordCount><abstractCharCount>1315</abstractCharCount><pdfWordCount>7437</pdfWordCount><pdfCharCount>47140</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>185</abstractWordCount></qualityIndicators><title>Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact</title><genre><json:string>research-article</json:string></genre><host><volume>132</volume><publisherId><json:string>brainj</json:string></publisherId><pages><last>2230</last><first>2219</first></pages><issn><json:string>0006-8950</json:string></issn><issue>8</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2156</json:string></eissn><title>Brain</title></host><categories><wos><json:string>CLINICAL NEUROLOGY</json:string><json:string>NEUROSCIENCES</json:string></wos></categories><publicationDate>2009</publicationDate><copyrightDate>2009</copyrightDate><doi><json:string>10.1093/brain/awp162</json:string></doi><id>BD4E2C9443B938FC3AECA5239FEA6837A5B171A4</id><score>0.23370779</score><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/BD4E2C9443B938FC3AECA5239FEA6837A5B171A4/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/BD4E2C9443B938FC3AECA5239FEA6837A5B171A4/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/BD4E2C9443B938FC3AECA5239FEA6837A5B171A4/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</p></availability><date>2009-07-02</date></publicationStmt><notesStmt><note>*These authors contribute equally to this work</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact</title><author xml:id="author-1"><persName><forename type="first">Benoit D.</forename><surname>Roussel</surname></persName><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation></author><author xml:id="author-2"><persName><forename type="first">Richard</forename><surname>Macrez</surname></persName><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation></author><author xml:id="author-3"><persName><forename type="first">Amandine</forename><surname>Jullienne</surname></persName><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation></author><author xml:id="author-4"><persName><forename type="first">Véronique</forename><surname>Agin</surname></persName><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation></author><author xml:id="author-5"><persName><forename type="first">Eric</forename><surname>Maubert</surname></persName><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation></author><author xml:id="author-6"><persName><forename type="first">Luce</forename><surname>Dauphinot</surname></persName><affiliation>2 Neurobiologie et Diversité Cellulaire, CNRS-UMR 7637, ESPCI, Paris, France</affiliation></author><author xml:id="author-7"><persName><forename type="first">Marie-Claude</forename><surname>Potier</surname></persName><affiliation>2 Neurobiologie et Diversité Cellulaire, CNRS-UMR 7637, ESPCI, Paris, France</affiliation></author><author xml:id="author-8"><persName><forename type="first">Laurent</forename><surname>Plawinski</surname></persName><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation></author><author xml:id="author-9"><persName><forename type="first">Hervé</forename><surname>Castel</surname></persName><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation></author><author xml:id="author-10"><persName><forename type="first">Yannick</forename><surname>Hommet</surname></persName><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation></author><author xml:id="author-11"><persName><forename type="first">Josep</forename><surname>Munuera</surname></persName><affiliation>3 Neuroimaging Unit, Department of Neuroradiology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain</affiliation></author><author xml:id="author-12"><persName><forename type="first">Joan</forename><surname>Montaner</surname></persName><affiliation>4 Neurovascular Research Laboratory, Stroke Unit, Department of Neurology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain</affiliation></author><author xml:id="author-13"><persName><forename type="first">Manuel</forename><surname>Yepes</surname></persName><affiliation>5 Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA30322, USA</affiliation></author><author xml:id="author-14" corresp="yes"><persName><forename type="first">Carine</forename><surname>Ali</surname></persName><email>ali@cyceron.fr</email><note type="biography">*These authors contribute equally to this work</note><affiliation>*These authors contribute equally to this work</affiliation><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation></author><author xml:id="author-15"><persName><forename type="first">Denis</forename><surname>Vivien</surname></persName><note type="biography">*These authors contribute equally to this work</note><affiliation>*These authors contribute equally to this work</affiliation><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation></author></analytic><monogr><title level="j">Brain</title><idno type="pISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-08"></date><biblScope unit="volume">132</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="2219">2219</biblScope><biblScope unit="page" to="2230">2230</biblScope></imprint></monogr><idno type="istex">BD4E2C9443B938FC3AECA5239FEA6837A5B171A4</idno><idno type="DOI">10.1093/brain/awp162</idno><idno type="ArticleID">awp162</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009-07-02</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Recombinant tissue-type plasminogen activator (tPA) is the fibrinolytic drug of choice to treat stroke patients. However, a growing body of evidence indicates that besides its beneficial thrombolytic role, tPA can also have a deleterious effect on the ischaemic brain. Although ageing influences stroke incidence, complications and outcome, age-dependent relationships between endogenous tPA and stroke injuries have not been investigated yet. Here, we report that ageing is associated with a selective lowering of brain tPA expression in the murine brain. Moreover, our results show that albumin D site-binding protein (DBP) as a key age-associated regulator of the neuronal transcription of tPA. Additionally, inhibition of DBP-mediated tPA expression confers in vitro neuroprotection. Accordingly, reduced levels of tPA in old mice are associated with smaller excitotoxic/ischaemic injuries and protection of the permeability of the neurovascular unit during cerebral ischaemia. Likewise, we provide neuroradiological evidence indicating the existence of an inverse relationship between age and the volume of the ischaemic lesion in patients with acute ischaemic stroke. Together, these results indicate that the relationship among DBP, tPA and ageing play an important role in the outcome of cerebral ischaemia.</p></abstract><textClass><keywords scheme="keyword"><list><item><term>Original Articles</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>ageing</term></item><item><term>tissue-type plasminogen activator</term></item><item><term>neurovascular unit</term></item><item><term>albumin D site-binding protein</term></item><item><term>stroke</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2009-07-02">Created</change><change when="2009-08">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/BD4E2C9443B938FC3AECA5239FEA6837A5B171A4/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">brain</journal-id><journal-id journal-id-type="publisher-id">brainj</journal-id><journal-title>Brain</journal-title><issn pub-type="ppub">0006-8950</issn><issn pub-type="epub">1460-2156</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/brain/awp162</article-id><article-id pub-id-type="publisher-id">awp162</article-id><article-categories><subj-group><subject>Original Articles</subject></subj-group></article-categories><title-group><article-title>Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Roussel</surname><given-names>Benoit D.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Macrez</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jullienne</surname><given-names>Amandine</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Agin</surname><given-names>Véronique</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Maubert</surname><given-names>Eric</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dauphinot</surname><given-names>Luce</given-names></name><xref ref-type="aff" rid="AFF2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Potier</surname><given-names>Marie-Claude</given-names></name><xref ref-type="aff" rid="AFF2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Plawinski</surname><given-names>Laurent</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Castel</surname><given-names>Hervé</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hommet</surname><given-names>Yannick</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Munuera</surname><given-names>Josep</given-names></name><xref ref-type="aff" rid="AFF3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Montaner</surname><given-names>Joan</given-names></name><xref ref-type="aff" rid="AFF4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yepes</surname><given-names>Manuel</given-names></name><xref ref-type="aff" rid="AFF5"><sup>5</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Ali</surname><given-names>Carine</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref><xref ref-type="fn" rid="FN1">*</xref></contrib><contrib contrib-type="author"><name><surname>Vivien</surname><given-names>Denis</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref><xref ref-type="fn" rid="FN1">*</xref></contrib></contrib-group><aff id="AFF1">1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</aff><aff id="AFF2">2 Neurobiologie et Diversité Cellulaire, CNRS-UMR 7637, ESPCI, Paris, France</aff><aff id="AFF3">3 Neuroimaging Unit, Department of Neuroradiology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain</aff><aff id="AFF4">4 Neurovascular Research Laboratory, Stroke Unit, Department of Neurology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain</aff><aff id="AFF5">5 Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA30322, USA</aff><author-notes><fn id="FN1"><p>*These authors contribute equally to this work </p></fn><corresp>Correspondence to: Carine Ali, INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS - Cyceron - Bd Becquerel, BP 5229 –14074 Caen, France E-mail: <email>ali@cyceron.fr</email></corresp></author-notes><pub-date pub-type="ppub"><month>8</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>2</day><month>7</month><year>2009</year></pub-date><volume>132</volume><issue>8</issue><fpage>2219</fpage><lpage>2230</lpage><history><date date-type="received"><day>17</day><month>10</month><year>2008</year></date><date date-type="rev-recd"><day>11</day><month>5</month><year>2009</year></date><date date-type="accepted"><day>12</day><month>5</month><year>2009</year></date></history><permissions><copyright-statement>© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2009</copyright-year></permissions><abstract><p>Recombinant tissue-type plasminogen activator (tPA) is the fibrinolytic drug of choice to treat stroke patients. However, a growing body of evidence indicates that besides its beneficial thrombolytic role, tPA can also have a deleterious effect on the ischaemic brain. Although ageing influences stroke incidence, complications and outcome, age-dependent relationships between endogenous tPA and stroke injuries have not been investigated yet. Here, we report that ageing is associated with a selective lowering of brain tPA expression in the murine brain. Moreover, our results show that albumin D site-binding protein (DBP) as a key age-associated regulator of the neuronal transcription of tPA. Additionally, inhibition of DBP-mediated tPA expression confers <italic>in vitro</italic> neuroprotection. Accordingly, reduced levels of tPA in old mice are associated with smaller excitotoxic/ischaemic injuries and protection of the permeability of the neurovascular unit during cerebral ischaemia. Likewise, we provide neuroradiological evidence indicating the existence of an inverse relationship between age and the volume of the ischaemic lesion in patients with acute ischaemic stroke. Together, these results indicate that the relationship among DBP, tPA and ageing play an important role in the outcome of cerebral ischaemia.</p></abstract><kwd-group><kwd>ageing</kwd><kwd>tissue-type plasminogen activator</kwd><kwd>neurovascular unit</kwd><kwd>albumin D site-binding protein</kwd><kwd>stroke</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact</title></titleInfo><name type="personal"><namePart type="given">Benoit D.</namePart><namePart type="family">Roussel</namePart><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Richard</namePart><namePart type="family">Macrez</namePart><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Amandine</namePart><namePart type="family">Jullienne</namePart><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Véronique</namePart><namePart type="family">Agin</namePart><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eric</namePart><namePart type="family">Maubert</namePart><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Luce</namePart><namePart type="family">Dauphinot</namePart><affiliation>2 Neurobiologie et Diversité Cellulaire, CNRS-UMR 7637, ESPCI, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marie-Claude</namePart><namePart type="family">Potier</namePart><affiliation>2 Neurobiologie et Diversité Cellulaire, CNRS-UMR 7637, ESPCI, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Laurent</namePart><namePart type="family">Plawinski</namePart><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hervé</namePart><namePart type="family">Castel</namePart><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yannick</namePart><namePart type="family">Hommet</namePart><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Josep</namePart><namePart type="family">Munuera</namePart><affiliation>3 Neuroimaging Unit, Department of Neuroradiology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Joan</namePart><namePart type="family">Montaner</namePart><affiliation>4 Neurovascular Research Laboratory, Stroke Unit, Department of Neurology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Manuel</namePart><namePart type="family">Yepes</namePart><affiliation>5 Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA30322, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Carine</namePart><namePart type="family">Ali</namePart><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation><affiliation>E-mail: ali@cyceron.fr</affiliation><description>*These authors contribute equally to this work</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Denis</namePart><namePart type="family">Vivien</namePart><affiliation>1 INSERM U919 ‘serine proteases and pathophysiology of the neurovascular unit’, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France; Université de Caen Basse-Normandie, Caen, F-14074, France</affiliation><description>*These authors contribute equally to this work</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><topic>Original Articles</topic></subject><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2009-08</dateIssued><dateCreated encoding="w3cdtf">2009-07-02</dateCreated><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Recombinant tissue-type plasminogen activator (tPA) is the fibrinolytic drug of choice to treat stroke patients. However, a growing body of evidence indicates that besides its beneficial thrombolytic role, tPA can also have a deleterious effect on the ischaemic brain. Although ageing influences stroke incidence, complications and outcome, age-dependent relationships between endogenous tPA and stroke injuries have not been investigated yet. Here, we report that ageing is associated with a selective lowering of brain tPA expression in the murine brain. Moreover, our results show that albumin D site-binding protein (DBP) as a key age-associated regulator of the neuronal transcription of tPA. Additionally, inhibition of DBP-mediated tPA expression confers in vitro neuroprotection. Accordingly, reduced levels of tPA in old mice are associated with smaller excitotoxic/ischaemic injuries and protection of the permeability of the neurovascular unit during cerebral ischaemia. Likewise, we provide neuroradiological evidence indicating the existence of an inverse relationship between age and the volume of the ischaemic lesion in patients with acute ischaemic stroke. Together, these results indicate that the relationship among DBP, tPA and ageing play an important role in the outcome of cerebral ischaemia.</abstract><note type="footnotes">*These authors contribute equally to this work</note><subject><genre>keywords</genre><topic>ageing</topic><topic>tissue-type plasminogen activator</topic><topic>neurovascular unit</topic><topic>albumin D site-binding protein</topic><topic>stroke</topic></subject><relatedItem type="host"><titleInfo><title>Brain</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0006-8950</identifier><identifier type="eISSN">1460-2156</identifier><identifier type="PublisherID">brainj</identifier><identifier type="PublisherID-hwp">brain</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>132</number></detail><detail type="issue"><caption>no.</caption><number>8</number></detail><extent unit="pages"><start>2219</start><end>2230</end></extent></part></relatedItem><identifier type="istex">BD4E2C9443B938FC3AECA5239FEA6837A5B171A4</identifier><identifier type="DOI">10.1093/brain/awp162</identifier><identifier type="ArticleID">awp162</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author (2009). 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