Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact.
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.
Roussel
Benoit D
BD
INSERM U919 serine proteases and pathophysiology of the neurovascular unit, UMR-CNRS 6232 CINAPS, Cyceron, Caen, F-14074 France.
Macrez
Richard
R
Jullienne
Amandine
A
Agin
Véronique
V
Maubert
Eric
E
Dauphinot
Luce
L
Potier
Marie-Claude
MC
Plawinski
Laurent
L
Castel
Hervé
H
Hommet
Yannick
Y
Munuera
Josep
J
Montaner
Joan
J
Yepes
Manuel
M
Ali
Carine
C
Vivien
Denis
D
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; D014157:Transcription Factors; D016202:N-Methylaspartate; D010959:Tissue Plasminogen Activator