Protease nexin-1, an antithrombin with neurite outgrowth activity, is reduced in Alzheimer disease.
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.
Wagner
S L
SL
Department of Microbiology and Molecular Genetics, University of California, Irvine 92717.
Geddes
J W
JW
Cotman
C W
CW
Lau
A L
AL
Gurwitz
D
D
Isackson
P J
PJ
Cunningham
D D
DD
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor; D001369:Axons / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis* / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D009928:Organ Specificity; D010960:Plasminogen Activators / Q000032:analysis*; D011480:Protease Inhibitors / Q000032:analysis*; D058255:Protease Nexins; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface; D012016:Reference Values; D058258:Serpin E2
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D011480:Protease Inhibitors; D058255:Protease Nexins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C545486:SERPINE2 protein, human; D058258:Serpin E2; D010960:Plasminogen Activators