Protease Nexin-1, an Antithrombin with Neurite Outgrowth Activity, is Reduced in Alzheimer Disease

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 86; no. 21; pp. 8284 - 8288
• Main Authors: Wagner, Steven L., Geddes, James W., Cotman, Carl W., Lau, Alice L., Gurwitz, David, Isackson, Paul J., Cunningham, Dennis D.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.11.1989; National Acad Sciences
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Alzheimers disease; Amyloid beta-Protein Precursor; Axons - physiology; Biochemistry; Biological and medical sciences; Brain; Brain - metabolism; Carrier Proteins - analysis; Carrier Proteins - genetics; Cultured cells; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Hippocampus; Hippocampus - metabolism; Homogenization; Humans; Immunoblotting; Medical sciences; Messenger RNA; Neurites; Neurology; Organ Specificity; Plasminogen Activators - analysis; Protease Inhibitors - analysis; Protease Nexins; Receptors, Cell Surface; Reference Values; RNA; RNA, Messenger - analysis; Serpin E2; thrombin; Visual cortex; Human; Brain; Nervous system diseases; Alzheimer disease; Gel electrophoresis; Enzyme; Proteinase; Enzyme inhibitor; Northern blotting; Enzymatic activity; Immunoblotting assay; Degenerative disease; Ratio; Comparative study
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.86.21.8284

Protease nexin-1 (PN-1) is a cell-secreted protein that inhibits certain proteases, particularly thrombin, by forming SDS-stable complexes with the catalytic site serine of the protease. PN-1 was recently shown to be identical to a glial-derived neurite-promoting factor/glial-derived nexin present in rat brain. Its neurite outgrowth activity depends on inhibition of thrombin, presumably because thrombin brings about neurite retraction. Here we show that human brain contains PN-1 and that PN-1 activity in brains of individuals with Alzheimer disease (AD) was only 14% of control values (total of 14 AD patients and 7 control individuals). PN-1 activity in the hippocampus, a region with marked neuropathology in AD, was 15% of control values (10 AD patients and 4 control individuals). Western blot analysis indicated a large decrease in free PN-1 protein and an increase in PN-1-containing complexes that comigrated with PN-1-thrombin complexes. Northern blot analysis indicated that PN-1 mRNA levels were about equal in brains from AD patients and control individuals. Thus these results suggest that the decreases in PN-1 activity and free PN-1 protein are due to formation of PN-1-protease complexes.