Tissue plasminogen activator requires plasminogen to modulate amyloid-β neurotoxicity and deposition

Tissue plasminogen (plgn) activator (tPA) modulates neuronal death in models of stroke, excitotoxicity, and oxidative stress. Amyloid-beta (A beta) appears central to Alzheimer's disease and is neurotoxic to neurons in vitro. Here, we evaluate tPA effects on A beta toxicity. We report that tPA alone had no effect on A beta toxicity. However, in combination with plgn, tPA reduced A beta toxicity in a robust fashion. Moreover, the combined tPA and plgn treatment markedly inhibited A beta accumulation. The addition of phenylmethylsulfonyl fluoride, a serine protease inhibitor, to a sample of tPA, plgn, and A beta resulted in a marked reduction of A beta degradation. We interpret the actions of tPA and plgn within the context of the ability of plasmin to degrade A beta.