Protease nexin I, thrombin- and urokinase-inhibiting serpin, concentrated in normal human cerebrospinal fluid

Abstract

Protease nexin I (PNI), a 43,000- to 50,000-dalton glycoprotein, is a potent thrombin and urokinase inhibitor produced by many mammalian cells, including human glia, in tissue culture. PNI is a member of the growing superfamily of serine protease inhibitors now known as serpins, but, unlike many others of this family, it has not yet been detected in normal human plasma. Of interest to neurobiology and neurologic disease, PNI is identical to a glia-derived neurite-promoting factor, glia-derived nexin (GDN). Antibody to PNI stains the periphery of senile amyloid plaques in brain tissue from patients with Alzheimer's disease (AD), along with another serpin, alpha 1-antichymotrypsin (alpha 1-ACT). A soluble form of the beta-amyloid precursor protein (beta APP), containing a Kunitz-type trypsin inhibitor domain, the beta APP751 form, is identical to protease nexin II (PNII), a 100,000-dalton serine protease inhibitor present in a number of tissues besides the brain. PNII/beta APP is also found in normal and AD CSF. We found a 47,000-dalton PNI, a thrombin- and urokinase-inhibiting serpin, in normal human CSF by Western blotting using a monospecific antibody. We also demonstrated biologically active PNI capable of forming complexes with serine proteases 125I-urokinase or 125I-thrombin.