Protease nexin-1, a potent thrombin inhibitor, is reduced around cerebral blood vessels in Alzheimer's disease

The clotting protease thrombin might contribute to the pathophysiology of central nervous system (CNS) injury and certain diseases by its ability to retract processes on neurons and astrocytes and to stimulate astrocyte proliferation. Protease nexin-1 (PN-1) is a 43 kDa thrombin inhibitor found predominantly in the brain where much of it resides around capillaries and large blood vessels. This location of PN-1 prompted the hypothesis that it may play a protective role against extravasated thrombin released following cerebrovascular injury or under certain pathological conditions. Recent studies indicated that the levels of PN-1 are markedly reduced in the postmortem brainsof patients with Alzheimer's disease (AD). It was suggested that this reduction in PN-1 levels was due to the sequestration of PN-1 by extravasated thrombin. In the present study we examined the specific nature of this reduction by immunohistochemical staining of sections from control and AD brains using PN-1 specific antibodies. We show that the levels of PN-1 immunoreactivity around vessels and the number of blood vessels exhibiting PN-1 immunoreactivity were markedly reduced in the brains of patients with AD compared to age-matched controls; this reduction was reflected by a decrease in the levels of PN-1 activity and PN-1 protein. Thus an imbalance between PN-1 and thrombin may be a contributing factor in the pathology of AD.