Figure 1.

tPA and uPA convert plasminogen to the active, broad-spectrum, protease plasmin both at the cell surface and in the immediate pericellular space. Plasmin, in turn, degrades target substrates (eg, APP, Aβ) directly as well as indirectly through downstream activation of matrix metalloproteinases (MMPs). Inhibition of MMP activity (GM6001, TIMP) has confirmed their participation in plasmin-initiated proteolysis. Most importantly, this cascade is effectively attenuated by overexpression (or exogenous addition) or PAI-1 which blocks tPA and uPA catalysis inhibiting, thereby, plasmin generation.