The Tissue Plasminogen Activator-Plasminogen Proteolytic Cascade Accelerates Amyloid-β (Aβ) Degradation and Inhibits Aβ-Induced Neurodegeneration

Melchor, Jerry P.; Pawlak, Robert; Strickland, Sidney

doi:10.1523/jneurosci.23-26-08867.2003

Cited by 209 publications

(220 citation statements)

References 35 publications

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“…[47][48][49] A downregulation of tPA activity is also evident in mouse models of AD, with several studies attributing the suppression of tPA activity to an increase in the expression of serine protease inhibitors. 25,48,50 Although we also show a decrease in tPA activity in the AD mouse brain, no obvious increases in the expression of the major inhibitors of tPA including PAI-1, PN-1 or neuroserpin was observed (Figure 6c). This dissimilarity may be because of the especially young age of the AD mice used in our study, as increases in PAI-1 levels 25 and decreases in tPA expression 51 arise at later stages in development.…”

Section: Discussionmentioning

confidence: 65%

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

Sashindranath

Samson

Downes

et al. 2011

Laboratory Investigation

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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 À/À 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.

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Section: Discussionmentioning

confidence: 65%

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

Sashindranath

Samson

Downes

et al. 2011

Laboratory Investigation

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“…APBA1 is a neuronal adaptor protein that interacts with, stabilizes and inhibits the proteolysis of the Alzheimer's disease amyloid precursor protein (APP) (30). A large number of genes involved in neurological disorders are present in the 207 genes of our expanded gene list which were not identified in the original 463 aging genes identified by Lu et al These include interesting genes implicated in age-specific neurological diseases, such as CDK5, CDK5R1, BCL2L1, and PLAT (30)(31)(32)(33). The full gene list is found in SI Table 2.…”

Section: Resultsmentioning

confidence: 99%

Multivariate regression analysis of distance matrices for testing associations between gene expression patterns and related variables

Zapala

Schork

2006

Proc. Natl. Acad. Sci. U.S.A.

259

241

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A fundamental step in the analysis of gene expression and other high-dimensional genomic data is the calculation of the similarity or distance between pairs of individual samples in a study. If one has collected N total samples and assayed the expression level of G genes on those samples, then an N ؋ N similarity matrix can be formed that reflects the correlation or similarity of the samples with respect to the expression values over the G genes. This matrix can then be examined for patterns via standard data reduction and cluster analysis techniques. We consider an alternative to conventional data reduction and cluster analyses of similarity matrices that is rooted in traditional linear models. This analysis method allows predictor variables collected on the samples to be related to variation in the pairwise similarity/distance values reflected in the matrix. The proposed multivariate method avoids the need for reducing the dimensions of a similarity matrix, can be used to assess relationships between the genes used to construct the matrix and additional information collected on the samples under study, and can be used to analyze individual genes or groups of genes identified in different ways. The technique can be used with any high-dimensional assay or data type and is ideally suited for testing subsets of genes defined by their participation in a biochemical pathway or other a priori grouping. We showcase the methodology using three published gene expression data sets.analysis of variance ͉ high-dimensional data

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“…tPA functions through both proteolytic and non-proteolytic pathways (Tsirka et al, 1997;Rogove et al, 1999;Nicole et al, 2001;Melchor et al, 2003). To determine whether tPA activity is crucial for the increase in NOS activity, we pharmacologically inhibited tPA in wild-type mice prior to the injection of KA using the synthetic tPA inhibitor tPA Stop, which successfully prevented the increase in NOS activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice

Parathath

Tsirka

2006

Journal of Cell Science

101

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Stroke and many neurodegenerative diseases culminate in neuronal death through a mechanism known as excitotoxicity. Excitotoxicity proceeds through a complex signaling pathway that includes the participation of the serine protease tissue plasminogen activator (tPA). tPA mediates neurotoxic effects on resident central nervous system cells as well alters blood-brain barrier (BBB) permeability, which further promotes neurodegeneration. Another signaling molecule that promotes neurodegeneration and BBB dysfunction is nitric oxide (NO), although its precise role in pathological progression remains unclear. We examine here the potentially interrelated roles of tPA, NO and peroxynitrite (ONOO–), which is the toxic metabolite of NO, in BBB breakdown and neurodegeneration following intrahippocampal injection of the glutamate analog kainite (KA). We find that NO and ONOO– production are linked to tPA-mediated excitotoxic injury, and demonstrate that NO provision suffices to restore the toxic effects of KA in tPA-deficient mice that are normally resistant to excitotoxicity. NO also promotes BBB breakdown and excitotoxicity. Interestingly, BBB breakdown in itself does not suffice to elicit neurodegeneration; a subsequent ONOO–-mediated event is required. In conclusion, NO and ONOO– function as downstream effectors of tPA-mediated excitotoxicity.

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The Tissue Plasminogen Activator-Plasminogen Proteolytic Cascade Accelerates Amyloid-β (Aβ) Degradation and Inhibits Aβ-Induced Neurodegeneration

Cited by 209 publications

References 35 publications

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

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

Multivariate regression analysis of distance matrices for testing associations between gene expression patterns and related variables

Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice

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