Physiological and pathological functions of neuroserpin: Regulation of cellular responses through multiple mechanisms.

It is 27 years since neuroserpin was first discovered in the nervous system and identified as a member of the serpin superfamily. Since that time potential roles for this serine protease inhibitor have been identified in neuronal and non-neuronal systems. Many are linked to inhibition of neuroserpin's principal enzyme target, tissue plasminogen activator (tPA), although some have been suggested to involve alternate non-inhibitory mechanisms. This review focuses mainly on the inhibitory roles of neuroserpin and discusses the evidence supporting tPA as the physiological target. While the major sites of neuroserpin expression are neural, endocrine and immune tissues, most progress on characterizing functional roles for neuroserpin have been in the brain. Roles in emotional behaviour, synaptic plasticity and neuroprotection in stroke and excitotoxicity models are discussed. Current knowledge on three neurological diseases associated with neuroserpin mutation or activity, Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB), Alzheimer's disease and brain metastasis is presented. Finally, we consider mechanistic studies that have revealed a distinct inhibitory mechanism for neuroserpin and its possible implications for neuroserpin function.

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

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.

AAV-mediated overexpression of neuroserpin in the hippocampus decreases PSD-95 expression but does not affect hippocampal-dependent learning and memory.

Neuroserpin is a serine protease inhibitor, or serpin, that is expressed in the nervous system and inhibits the protease tissue plasminogen activator (tPA). Neuroserpin has been suggested to play a role in learning and memory but direct evidence for such a role is lacking. Here we have used an adeno-associated virus (AAV) vector expression system to investigate the effect of neuroserpin on hippocampal-dependent learning and memory in the young adult rat. A FLAG-tagged neuroserpin construct was initially characterized by in vitro transcription/translation and transfection into HEK293 cells and shown to interact with tPA and be targeted to the secretory pathway. Targeted injection of a chimeric AAV1/2 vector expressing FLAG-neuroserpin resulted in localized overexpression in the dorsal hippocampus. Neuroserpin overexpression led to the appearance of an unstable neuroserpin:tPA complex in zymographic assays consistent with interaction with endogenous tPA in vivo. Rats overexpressing neuroserpin also showed a significant decrease in the levels of postsynaptic density protein 95, a major postsynaptic scaffolding protein. Three weeks after injection, a range of behavioural tests was performed to measure spatial and associative learning and memory, as well as innate and acquired fear. These tests provided no evidence of a role for neuroserpin in hippocampal-dependent learning and memory. In summary this study does not support a role for neuroserpin in hippocampal-dependent learning and memory in young adult rats but does suggest an involvement of neuroserpin in hippocampal synaptic plasticity.

Synaptic plasticity-associated proteases and protease inhibitors in the brain linked to the processing of extracellular matrix and cell adhesion molecules.

Research on the molecular and cellular basis of learning and memory has focused on the mechanisms that underlie the induction and expression of synaptic plasticity. There is increasing evidence that structural changes at the synapse are associated with synaptic plasticity and that extracellular matrix (ECM) components and cell adhesion molecules are associated with these changes. The functions of both groups of molecules can be regulated by proteolysis. In this article we review the roles of selected proteases and protease inhibitors in perisynaptic proteolysis of the ECM and synaptic adhesion proteins and the impact of proteolysis on synaptic modification and cognitive function.