Tissue‐type plasminogen activator rescues neurones from serum deprivation‐induced apoptosis through a mechanism independent of its proteolytic activity

Abstract

Although the mechanism of action of tissue-type plasminogen activator (tPA) in excitotoxic necrosis is well documented, whether this serine protease can influence the apoptotic cascade remains a subject of debate. Here, we report that tPA protects cultured cortical neurones against apoptotic cell death induced by serum deprivation, an effect associated with a reduction of caspase-3 activation. Interestingly, blocking tPA proteolytic activity by either tPA stop or neuroserpin did not prevent this neuroprotection. Similarly, prevention of the interaction between tPA and its receptor low-density lipoprotein receptor-related protein (LRP) could not alter tPA anti-apoptotic activity. Interestingly, the survival-promoting effect of tPA was blocked by the phosphatidylinositol-3 (PI-3) kinase inhibitor, LY294002, but not by the mitogen-activated protein (MAP) kinase inhibitor, U0126. In conclusion, the present demonstration of an anti-apoptotic effect of tPA, independent of its enzymatic activity, reveals an additional level of complexity in our understanding of this critical mediator of brain physiology and pathology.

NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity

“…As MK-801-induced blockage of basal NMDAR signalling was earlier shown to induce apoptotic neuronal death, 38 we can postulate that in such conditions, tPA could display a neurotrophic activity, which fits well with its earlier shown non-proteolytic anti-apoptotic effect. 39 In pathological scenarios such as ischemia, Ca 2 þ influx through the NMDAR is a key mediator of cell death. However, physiological levels of NMDAR activity can promote neuronal survival and resistance to trauma and have important functions in synaptic plasticity and transmission.…”

Impact of Tissue Plasminogen Activator on the Neurovascular Unit: From Clinical Data to Experimental Evidence

“…It is also interesting to note that NMDA-dependent nitric oxide production has been recently demonstrated to be dependent on tPA (Parathath et al, 2006), unveiling a possible role of tPA in the control of local cerebral perfusion. In contrast to its well-admitted exacerbating effect on neuronal excitotoxic necrosis (Nolin et al, 2008), tPA modulates apoptotic neuronal (Liot et al, 2006) and oligodendrocyte death independently of its proteolytic activity (Correa et al, 2011). Together with the previous observations that nonproteolytically active tPA can activate microglia after binding to annexin II (Siao and Tsirka, 2002), these antiapoptotic mechanisms of tPA strongly support the notion of a 'cytokine-like' or even 'neurotrophic-like' function of this molecule.…”

Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism

“…These data are in agreement with previous demonstrations that exogenous tPA may have either proneurotoxic or prosurvival effects depending on the type of paradigm, on the type of neurons (hippocampal versus cortical) or on the model used (wild-type neurons, tPAdeficient neurons, tPA overexpressing neurons in vitro and in vivo). 11,13,17,[19][20][21] Thus, as reported previously, 19,20 we can postulate that, when released by suffering neurons at low concentrations, the endogenous tPA displays neuroprotective effects.…”

“…This deleterious effect of tPA could be explained either by a differential sensitivity of the DG to tPA under ischemic conditions or to a different mechanism of neuronal death when subjected to OGD (excitotoxicity versus apoptosis). Indeed, although tPA is protective in an apoptotic paradigm, 17 it is deleterious in a context of excitotoxicity.…”

“…12 Several studies showed that tPA can promote neurotoxicity, 5,13 especially by an overactivation of NMDARs. 8,11,[14][15][16] However, tPA may also display prosurvival properties on neurons and oligodendrocytes 4,6,[17][18][19][20] involving either an EGFR-dependent signaling, 6 binding to Annexin-II 18 or active NMDARs. 20 Interestingly, although the proneurotoxic effects of tPA were reported for exogenous tPA 11,21 or based on data obtained from tPA-deficient mice, 13 neurotrophic effects were mainly reported for endogenous tPA 19 or from experiments performed on tPA overexpressing animals.…”