Physiological and pathological roles of tissue plasminogen activator and its inhibitor neuroserpin in the nervous system

Abstract

Although its roles in the vascular space are most well-known, tissue plasminogen activator (tPA) is widely expressed in the developing and adult nervous system, where its activity is believed to be regulated by neuroserpin, a predominantly brain-specific member of the serpin family of protease inhibitors. In the normal physiological state, tPA has been shown to play roles in the development and plasticity of the nervous system. Ischemic damage, however, may lead to excess tPA activity in the brain and this is believed to contribute to neurodegeneration. In this article, we briefly review the physiological and pathological roles of tPA in the nervous system, which includes neuronal migration, axonal growth, synaptic plasticity, neuroprotection and neurodegeneration, as well as a contribution to neurological disease. We summarize tPA's multiple mechanisms of action and also highlight the contributions of the inhibitor neuroserpin to these processes.

Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury

“…As a potential mechanism underlying axonal sprouting, EGFR activation mediated tPA-induced axonal extension in cultured primary cortical neurons after exposure to CSPG. Endogenous tPA is known to be released in an activity-dependent manner from neurons after exposure to stimuli associated with synaptic plasticity and is critical for long-term potentiation (10,11,40,41). These collective observations suggest that superior neuroplasticity under conditions of tPA repletion may facilitate improvements in long-term outcomes.…”

“…However, the role of endogenous tPA in acute brain injuries is somewhat controversial. For example, tPA is hypothesized to augment blood-brain barrier damage, edema, and hemorrhage in models of acute brain injury (10)(11)(12)(13)(14)(15)(16). On the other hand, endogenous tPA also appears to protect neurons and white matter against acute ischemic insults (17,18).…”

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

“…The beneficial and deleterious effects of tPA in the CNS are time-dependent and involve diverse mechanisms. For readers who are interested in more details about the pleiotropic effects of tPA in the CNS, please read other reviews 20–22 .…”

Plasmin and regulators of plasmin activity control the migratory capacity and adhesion of human T cells and dendritic cells by regulating cleavage of the chemokine CCL21

“…Plasmin activity is also tightly regulated through direct inhibitors such as α 2 ‐antiplasmin and through the upstream regulation of the activating proteases tPA and uPA 29 . PAI‐1 (serpin E1) and neuroserpin (serpin I1), inhibitors of tPA, are both members of the serine protease inhibitor (serpin) family, a group of proteins defined by their conserved structure and their ability to inhibit serine proteases 30 , 31 , 32 . Neuroserpin strongly inhibits tPA and, to a lesser extent, uPA 33 , 34 …”

“…29 PAI-1 (serpin E1) and neuroserpin (serpin I1), inhibitors of tPA, are both members of the serine protease inhibitor (serpin) family, a group of proteins defined by their conserved structure and their ability to inhibit serine proteases. [30][31][32] Neuroserpin strongly inhibits tPA and, to a lesser extent, uPA. 33,34 In the present study we show that plasmin cleaves the C terminus of CCL21 to convert it from a surface-bound to a soluble form and that plasmin, tPA and α 2 -antiplasmin modulate CCL21-mediated cell migration and CCL21-dependent cell tethering.…”