SERINE-PROTEASE INHIBITOR ANTITHROMBIN-III AND ITS MESSENGER-RNA IN THE PATHOGENESIS OF ALZHEIMERS-DISEASE

The classical plasma protein antithrombin III (ATIII), an inhibitor of the blood coagulation cascade, is a member of the serpins that are ga ining import in the nervous system. In this study, we examined the pre sence of ATIII in the pathological lesions of Alzheimer's disease (AD) . Antibodies to ATIII consistently detected approximately 58-kd protei n(s) on immunoblots of cerebral cortex and brain microvessels. Immunoc ytochemical studies showed ATIII reactivity within amyloid deposits, n eurites associated with plaques, and neurofibrillary tangles in neocor tex and hippocampus of virtually all the AD cases examined. In some ca ses, astrocytes were also stained, suggesting ATIII in these cells. AT III immunoreactivity in neurofibrillary tangles was further defined by electron microscopy, which showed it to be associated with paired hel ical filaments. Using the polymerase chain reaction technique to ampli fy ATIII complementary DNA, we found low levels of messenger RNA expre ssion, relative to liver, in control human brain samples, and these we re increased in AD samples, particularly in the white matter. Our resu lts suggest the increased presence of ATIII commensurate with astrogli osis and association with the neurofibrillary pathology of AD. We conc lude that in concert with other amyloid-associated serine protease inh ibitors, ATIII may play a role in the pathogenesis of cerebral amylido sis.