Serine protease inhibitor antithrombin III and its messenger RNA in the pathogenesis of Alzheimer's disease.
The classical plasma protein antithrombin III (ATIII), an inhibitor of the blood coagulation cascade, is a member of the serpins that are gaining import in the nervous system. In this study, we examined the presence of ATIII in the pathological lesions of Alzheimer's disease (AD). Antibodies to ATIII consistently detected approximately 58-kd protein(s) on immunoblots of cerebral cortex and brain microvessels. Immunocytochemical studies showed ATIII reactivity within amyloid deposits, neurites associated with plaques, and neurofibrillary tangles in neocortex and hippocampus of virtually all the AD cases examined. In some cases, astrocytes were also stained, suggesting ATIII in these cells. ATIII immunoreactivity in neurofibrillary tangles was further defined by electron microscopy, which showed it to be associated with paired helical filaments. Using the polymerase chain reaction technique to amplify ATIII complementary DNA, we found low levels of messenger RNA expression, relative to liver, in control human brain samples, and these were increased in AD samples, particularly in the white matter. Our results suggest the increased presence of ATIII commensurate with astrogliosis and association with the neurofibrillary pathology of AD. We conclude that in concert with other amyloid-associated serine protease inhibitors, ATIII may play a role in the pathogenesis of cerebral amyloidosis.
Kalaria
R N
RN
Department of Neurology and of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio.
Golde
T
T
Kroon
S N
SN
Perry
G
G
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000990:Antithrombin III / Q000032:analysis* / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000473:pathology / Q000648:ultrastructure; D001923:Brain Chemistry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000032:analysis*
D012333:RNA, Messenger; D000990:Antithrombin III