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Background Plasminogen activator inhibitor 1 (PAI-1) is a key regulator of the plasminogen activation system. Although several lines of evidence support a significant role of PAI-1 in the brain, the regulation of its expression in neurons is poorly understood.

In the present study we tested the hypothesis that NGF induces the upregulation of PAI-1 via the calcineurin/nuclear factor of activated T cells (NFAT) pathway and analysed whether the overexpression of the Down syndrome-related proteins DYRK1A and RCAN1 modulated the effect of NGF on PAI-1 expression. Results NGF upregulated PAI-1 mRNA levels in primary mouse hippocampal neurons cultured for 3 days in vitro and in the rat pheochromocytoma cell line PC12. Reporter gene assays revealed that NGF activated the calcineurin/NFAT pathway in PC12 cells. Induction of PAI-1 by NGF was sensitive to the calcineurin inhibitor FK506 and the specific inhibition of NFAT activation by the cell permeable VIVIT peptide.

Activation of calcineurin/NFAT signalling through other stimuli resulted in a much weaker induction of PAI-1 expression, suggesting that other NGF-induced pathways are involved in PAI-1 upregulation. Overexpression of either DYRK1A or RCAN1 negatively regulated NFAT-dependent transcriptional activity and reduced the upregulation of PAI-1 levels by NGF. Introduction The serine protease inhibitor plasminogen activator inhibitor-1 (PAI-1) is a component of the plasminogen activation system. Name Tag Psd more.

PAI-1 forms stable complexes with both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) and thus prevents the activation of plasminogen to plasmin. PAI-1 is expressed in a variety of tissues including the brain. As a regulator of plasminogen activation, PAI-1 is involved in the degradation of the extracellular matrix, which is important for synaptic remodelling, as well as in the regulation of the plasmin-mediated cleavage of proBDNF to BDNF.

As a tPA inhibitor, PAI-1 protects neurons from the tPA potentiation of the NMDA-induced calcium influx and necrosis. PAI-1 has also a neurotrophic/neuroprotective role in PC12 cells, which has been suggested to be independent of the plasminogen activation system. During the last decade PAI-1 has also attracted increasing attention for its potential function in Alzheimer disease both as a neurotrophic factor and as an inhibitor of plasmin’s α-secretase cleavage activity,. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a protein kinase member of the DYRK family that phosphorylates serine and threonine residues in its substrates and autophosphorylates a tyrosine residue in its activation loop.

The human DYRK1A gene is located on chromosome 21 and its overexpression is considered to be related to Down syndrome phenotypes. Both murine Dyrk1A and human DYRK1A genes are expressed in several regions of the brain,,, where they play a role in neuronal development and adult brain function. Transgenic mice that carry an extra copy of the Dyrk1A gene exhibit neurodevelopmental delay, motor abnormalities and cognitive deficits that resemble those described in Down syndrome individuals,,. Regulator of calcineurin 1 (RCAN1), which was formerly known as DSCR1 or calcipressin 1, binds to and inhibits the protein phosphatase calcineurin and its signalling pathways. The RCAN1 gene is also located on the human chromosome 21, is highly expressed in the human brain and is considered to be associated with Down syndrome traits. RCAN1 overexpression in transgenic mice affects the visuo-spatial learning and memory tasks and causes structural brain abnormalities in those areas affected in DS,. NFAT is a family of transcription factors consisting of the five members NFAT1–5. Sangeetha Bala Padam English Book Pdf.