Tissue-type plasminogen activator protects neurons from excitotoxin-induced cell death via activation of the ERK 1/2–CREB–ATF3 signaling pathway

Abstract

The release of the serine proteinase tissue-type plasminogen activator (tPA) from cerebral cortical neurons has a neuroprotective effect in the ischemic brain. Because excitotoxicity is a basic mechanism of ischemia-induced cell death here we investigated the effect of tPA on excitotoxin-induced neuronal death. We report that genetic overexpression of neuronal tPA or treatment with recombinant tPA renders neurons resistant to the harmful effects of an excitotoxic injury in vitro and in vivo. We found that at concentrations found in the ischemic brain tPA interacts with synaptic but not extrasynaptic NMDARs. This effect is independent of tPA’s proteolytic properties and leads to a rapid and transient phosphorylation of the extracellular signal regulated kinases 1 / 2 (ERK ½), with ERK ½-mediated activation of the cAMP response element binding protein (CREB) and induction of the neuroprotective CREB-regulated activating transcription factor 3 (Atf3). In line with these observations, Atf3 down-regulation abrogates the protective effect of tPA against excitotoxin-induced neuronal death. Our data indicate that tPA preferentially activates synaptic NMDARs via a plasminogen-independent mechanism turning on a cell signaling pathway that protects neurons from the deleterious effects of excitotoxicity.

Urokinase-Type Plasminogen Activator Promotes Dendritic Spine Recovery and Improves Neurological Outcome Following Ischemic Stroke

“…According to their morphology, dendritic protrusions are classified in filopodia, short spines without a well defined neck, and spines with a large bulbous head (Hering and Sheng, 2001). In the developing brain dendritic spines arise from filopodia (Xu et al, 2009). Our data are in agreement with reports by other groups (Brown et al, 2008) and suggest that in the peri-infarct cortex of the adult brain the formation of filopodia is a transient event that temporally precedes the re-emergence of dendritic spines.…”

“…To quantify the extent of vasogenic edema Wt and uPA Ϫ/Ϫ mice (n ϭ 8 per strain) were intravenously injected with 1 ml of Evans blue dye immediately after tMCAO. Twentyfour hours later animals were transcardially perfused, brains were harvested, and the concentration of Evans blue dye was quantified as described previously (Yepes et al, 2003).…”

Tissue-type plasminogen activator induces synaptic vesicle endocytosis in cerebral cortical neurons

“…The serine proteinase tissue-type plasminogen activator (tPA) is abundantly expressed in neurons (Samson and Medcalf, 2006), and its rapid release from the presynaptic terminal promotes the development of synaptic plasticity (Qian et al, 1993, Seeds et al, 1995, Muller and Griesinger, 1998, Pawlak et al, 2003), neuronal survival (Echeverry et al, 2010, Haile et al, 2012, Wu et al, 2013a), adaptation to metabolic stress (Wu et al, 2012, Wu et al, 2013b), and neuroglial coupling (An et al, 2014). TPA is found in the presynaptic terminal of cerebral cortical neurons, either intermixed with clear-core SVs of the reserve and recycling pools, or in direct contact with the presynaptic membrane (Wu, 2015).…”

LRP1 Assembles Unique Co-receptor Systems to Initiate Cell Signaling in Response to Tissue-type Plasminogen Activator and Myelin-associated Glycoprotein

“…tPA also may be transported across the blood-brain barrier by LDL receptor-related protein-1 (LRP1) (4). It is thus important to understand the numerous effects of tPA on neuronal cell biology and function, including effects on long term potentiation (5-7), excitotoxic neurotoxicity (3,8), axonal regrowth following injury (9), neuroprotection in hypoxia and ischemia (10,11), and permeability of the bloodbrain barrier (12).…”