Elsevier

Laboratory Investigation

Volume 91, Issue 7, July 2011, Pages 1079-1091
Laboratory Investigation

Research Article
Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

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Abstract

Tissue-type plasminogen activator (tPA) is a major protease of the central nervous system. Most studies to date have used in situ- or gel-based zymographic assays to monitor in vivo changes in neural tPA activity. In this study, we demonstrate that the amidolytic assay can be adapted to accurately detect changes in net tPA activity in mouse brain tissues. Using the amidolytic assay, we examined differences in net tPA activity in the cerebral cortex, sub-cortical structures and cerebellum in wildtype (WT) and tPA−/− mice, and in transgenic mice selectively overexpressing tPA in neurons. In addition, we assessed changes in endogenous net tPA activity in WT mice following morphine administration, epileptic seizures, traumatic brain injury and ischaemic stroke—neurological settings in which tPA has a known functional role. Under these conditions, acute and compartment-specific regulation of tPA activity was observed. tPA also participates in various forms of chronic neurodegeneration. Accordingly, we assessed tPA activity levels in mouse models of Alzheimer's disease (AD) and spinocerebellar ataxia type-1 (SCA1). Decreased tPA activity was detected in the cortex and subcortex of AD mice, whereas increased tPA activity was found in the cerebellum of SCA1 mice. These findings extend the existing hypotheses that low tPA activity promotes AD, whereas increased tPA activity contributes to cerebellar degeneration. Collectively, our results exemplify the utility of the amidolytic assay and emphasise tPA as a complex mediator of brain function and dysfunction. On the basis of this evidence, we propose that alterations in tPA activity levels could be used as a biomarker for perturbations in brain homeostasis.

KEYWORDS

alzheimer's disease
amidolytic assay
head trauma
morphine
seizure
spinocerebellar ataxia
stroke
tissue-type plasminogen activator

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Supplementary Information accompanies the paper on the Laboratory Investigation website

Maithili Sashindranath and Andre Laval Samson: These authors contributed equally to this work.

Alterations in tissue-type plasminogen activator (tPA), a major protease of the central nervous system, may be a biomarker for perturbations in brain homeostasis. Differences in net tPA activity in the cerebral cortex, sub-cortical structures and cerebellum in wild type and tPA-/- mice, and in transgenic mice selectively overexpressing tPA in neurons are demonstrated.

Supplementary information The online version of this article (doi:10.1038/labinvest.2011.67) contains supplementary material, which is available to authorized users.