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Brain Advance Access originally published online on July 2, 2009
Brain 2009 132(8):2219-2230; doi:10.1093/brain/awp162
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© 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

Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact

Benoit D. Roussel1, Richard Macrez1, Amandine Jullienne1, Véronique Agin1, Eric Maubert1, Luce Dauphinot2, Marie-Claude Potier2, Laurent Plawinski1, Hervé Castel1, Yannick Hommet1, Josep Munuera3, Joan Montaner4, Manuel Yepes5, Carine Ali1,* and Denis Vivien1,*

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 2 Neurobiologie et Diversité Cellulaire, CNRS-UMR 7637, ESPCI, Paris, France 3 Neuroimaging Unit, Department of Neuroradiology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain 4 Neurovascular Research Laboratory, Stroke Unit, Department of Neurology, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain 5 Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA30322, USA

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: ali{at}cyceron.fr

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.

Key Words: ageing; tissue-type plasminogen activator; neurovascular unit; albumin D site-binding protein; stroke

Abbreviations: DBP, albumin D site-binding protein; MCAO, middle cerebral artery occlusion; NMDA, N-methyl-D-aspartate; tPA, tissue-type plasminogen activator; WT, wild-type

.

Received October 17, 2008. Revised May 11, 2009. Accepted May 12, 2009.

*These authors contribute equally to this work


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