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Tissue-type plasminogen activator is a neuroprotectant in the central nervous system.

Yepes M - Front Cell Neurosci (2015)

Bottom Line: Tissue-type plasminogen activator (tPA) is a serine proteinase found not only in the intravascular space but also in a well-defined sub-set of neurons in the brain. tPA is rapidly released from neurons after either exposure to hypoxia or hypoglycemia in vitro, or the induction of cerebral ischemia in vivo.More specifically, the non-proteolytic interaction of tPA with N-methyl-D-aspartate receptors (NMDARs) and a member of the low-density lipoprotein receptor (LDLR) family in dendritic spines activates the mammalian target of rapamycin (mTOR) pathway that adapts cellular processes to the availability of energy and metabolic resources.TPA-induced mTOR activation in neurons leads to hypoxia-inducible factor 1α (HIF-1α) accumulation, HIF-1α-induced expression and membrane recruitment of the neuronal transporter of glucose GLUT3, and GLUT3-mediated uptake of glucose.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine and Veterans Affairs Medical Center Atlanta, GA, USA.

ABSTRACT
Tissue-type plasminogen activator (tPA) is a serine proteinase found not only in the intravascular space but also in a well-defined sub-set of neurons in the brain. tPA is rapidly released from neurons after either exposure to hypoxia or hypoglycemia in vitro, or the induction of cerebral ischemia in vivo. It has been proposed that tPA has a neurotoxic effect in the ischemic brain. However, recent evidence indicate that once released into the synaptic cleft tPA activates specific cell signaling pathways that promote the detection and adaptation to metabolic stress. More specifically, the non-proteolytic interaction of tPA with N-methyl-D-aspartate receptors (NMDARs) and a member of the low-density lipoprotein receptor (LDLR) family in dendritic spines activates the mammalian target of rapamycin (mTOR) pathway that adapts cellular processes to the availability of energy and metabolic resources. TPA-induced mTOR activation in neurons leads to hypoxia-inducible factor 1α (HIF-1α) accumulation, HIF-1α-induced expression and membrane recruitment of the neuronal transporter of glucose GLUT3, and GLUT3-mediated uptake of glucose. These and other data discussed in this Review suggest that the postulated neurotoxic effect of tPA needs to be reconsidered and instead indicate the emergence of a new paradigm: that tPA is an endogenous neuroprotectant in the central nervous system (CNS).

No MeSH data available.


Related in: MedlinePlus

Proposed mechanism for tPA-induced neuroprotection. Tissue-type plasminogen activator (tPA) either released from the presynaptic terminal (red circles) or given as a treatment (rtPA; red circles with a black margin) interact with a co-receptor formed by the low density lipoprotein receptor-related protein (LRP1; orange line) and the NMDA receptor (yellow squares) on the surface of the dendritic spine (post-synaptic compartment), leading to mTOR activation and mTOR-induced synthesis of the glucose transporter GLU3 (orange arrows) with the resultant increase in the uptake of glucose (green triangles).
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Figure 1: Proposed mechanism for tPA-induced neuroprotection. Tissue-type plasminogen activator (tPA) either released from the presynaptic terminal (red circles) or given as a treatment (rtPA; red circles with a black margin) interact with a co-receptor formed by the low density lipoprotein receptor-related protein (LRP1; orange line) and the NMDA receptor (yellow squares) on the surface of the dendritic spine (post-synaptic compartment), leading to mTOR activation and mTOR-induced synthesis of the glucose transporter GLU3 (orange arrows) with the resultant increase in the uptake of glucose (green triangles).

Mentions: Based on these data and other results not discussed here (An et al., 2014), we propose a model whereby tPA either released in the synaptic cleft following the onset of cerebral ischemia or intravenously administered interacts with LRP1, leading to NMDAR-mediated mTOR activation, mTOR-induced HIF-1α accumulation, HIF-1α-induced recruitment of the neuronal transporter of glucose GLUT3 to the neuronal plasma membrane, and GLUT3-mediated uptake of glucose by neurons in the ischemic brain (Figure 1). In summary, here we propose a mechanistic model whereby tPA is a neuroprotectant in the ischemic brain by its ability to promote the detection and adaptation to the metabolic stress triggered by the lack of oxygen and glucose.


Tissue-type plasminogen activator is a neuroprotectant in the central nervous system.

Yepes M - Front Cell Neurosci (2015)

Proposed mechanism for tPA-induced neuroprotection. Tissue-type plasminogen activator (tPA) either released from the presynaptic terminal (red circles) or given as a treatment (rtPA; red circles with a black margin) interact with a co-receptor formed by the low density lipoprotein receptor-related protein (LRP1; orange line) and the NMDA receptor (yellow squares) on the surface of the dendritic spine (post-synaptic compartment), leading to mTOR activation and mTOR-induced synthesis of the glucose transporter GLU3 (orange arrows) with the resultant increase in the uptake of glucose (green triangles).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4538299&req=5

Figure 1: Proposed mechanism for tPA-induced neuroprotection. Tissue-type plasminogen activator (tPA) either released from the presynaptic terminal (red circles) or given as a treatment (rtPA; red circles with a black margin) interact with a co-receptor formed by the low density lipoprotein receptor-related protein (LRP1; orange line) and the NMDA receptor (yellow squares) on the surface of the dendritic spine (post-synaptic compartment), leading to mTOR activation and mTOR-induced synthesis of the glucose transporter GLU3 (orange arrows) with the resultant increase in the uptake of glucose (green triangles).
Mentions: Based on these data and other results not discussed here (An et al., 2014), we propose a model whereby tPA either released in the synaptic cleft following the onset of cerebral ischemia or intravenously administered interacts with LRP1, leading to NMDAR-mediated mTOR activation, mTOR-induced HIF-1α accumulation, HIF-1α-induced recruitment of the neuronal transporter of glucose GLUT3 to the neuronal plasma membrane, and GLUT3-mediated uptake of glucose by neurons in the ischemic brain (Figure 1). In summary, here we propose a mechanistic model whereby tPA is a neuroprotectant in the ischemic brain by its ability to promote the detection and adaptation to the metabolic stress triggered by the lack of oxygen and glucose.

Bottom Line: Tissue-type plasminogen activator (tPA) is a serine proteinase found not only in the intravascular space but also in a well-defined sub-set of neurons in the brain. tPA is rapidly released from neurons after either exposure to hypoxia or hypoglycemia in vitro, or the induction of cerebral ischemia in vivo.More specifically, the non-proteolytic interaction of tPA with N-methyl-D-aspartate receptors (NMDARs) and a member of the low-density lipoprotein receptor (LDLR) family in dendritic spines activates the mammalian target of rapamycin (mTOR) pathway that adapts cellular processes to the availability of energy and metabolic resources.TPA-induced mTOR activation in neurons leads to hypoxia-inducible factor 1α (HIF-1α) accumulation, HIF-1α-induced expression and membrane recruitment of the neuronal transporter of glucose GLUT3, and GLUT3-mediated uptake of glucose.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine and Veterans Affairs Medical Center Atlanta, GA, USA.

ABSTRACT
Tissue-type plasminogen activator (tPA) is a serine proteinase found not only in the intravascular space but also in a well-defined sub-set of neurons in the brain. tPA is rapidly released from neurons after either exposure to hypoxia or hypoglycemia in vitro, or the induction of cerebral ischemia in vivo. It has been proposed that tPA has a neurotoxic effect in the ischemic brain. However, recent evidence indicate that once released into the synaptic cleft tPA activates specific cell signaling pathways that promote the detection and adaptation to metabolic stress. More specifically, the non-proteolytic interaction of tPA with N-methyl-D-aspartate receptors (NMDARs) and a member of the low-density lipoprotein receptor (LDLR) family in dendritic spines activates the mammalian target of rapamycin (mTOR) pathway that adapts cellular processes to the availability of energy and metabolic resources. TPA-induced mTOR activation in neurons leads to hypoxia-inducible factor 1α (HIF-1α) accumulation, HIF-1α-induced expression and membrane recruitment of the neuronal transporter of glucose GLUT3, and GLUT3-mediated uptake of glucose. These and other data discussed in this Review suggest that the postulated neurotoxic effect of tPA needs to be reconsidered and instead indicate the emergence of a new paradigm: that tPA is an endogenous neuroprotectant in the central nervous system (CNS).

No MeSH data available.


Related in: MedlinePlus