PROTEASE NEXIN-1, A POTENT THROMBIN INHIBITOR, IS REDUCED AROUND CEREBRAL BLOOD-VESSELS IN ALZHEIMERS-DISEASE

The clotting protease thrombin might contribute to the pathophysiology of central nervous system (CNS) injury and certain diseases by its ab ility 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 ar ound capillaries and large blood vessels. This location of PN-1 prompt ed the hypothesis that it may play a protective role against extravasa ted thrombin released following cerebrovascular injury or under certai n pathological conditions. Recent studies indicated that the levels of PN-1 are markedly reduced in the postmortem brains of patients with A lzheimer'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 brain s using PN-1 specific antibodies. We show that the levels of PN-1 immu noreactivity around blood vessels and the number of blood vessels exhi biting PN-1 immunoreactivity were markedly reduced in the brains of pa tients with AD compared to age-matched controls; this reduction was re flected 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 fac tor in the pathology of AD.