Plasminogen activator inhibition in Alzheimer disease brain

Abstract

Amyloid beta (Aβ) plaques are a pathological hallmark of Alzheimer's disease (AD). Several proteases are known to cleave Aβ including plasmin, the product of tissue plasminogen activator (tPA) cleavage of the pro‐enzyme plasminogen. Although several in vitro studies have demonstrated a clear link between the PA/plasmin system and AD, there has been little analysis of the PA/plasmin system in the brains of AD patients. In this study, we utilized zymography and immunocapture assays to determine the tPA activity in frontal cortex tissue of AD patients. The amount of active tPA is significantly reduced (~50%) in brain homogenates of AD patients compared to age‐matched controls. Interestingly, western blot analysis showed that both tPA and plasminogen protein levels were similar between the AD and control brain tissues; suggesting that tPA activity was inhibited in the AD brain. An analysis of endogenous PA inhibitors showed that while plasminogen activator inhibitor‐1 levels were unchanged, neuroserpin levels were significantly elevated (1.6‐fold) in brains of AD patients. Immunohistochemical studies demonstrate that both tPA and neuroserpin protein are associated with Aβ plaques in the AD brain tissue, providing further support for our hypothesis. Thus, neuroserpin inhibition of tPA activity explains the lower plasmin levels and possibly the Aβ accumulation seen in AD brain tissue. Neuroserpin may be a target for AD therapy.