The plasmin system is induced by and degrades amyloid-beta aggregates

Amyloid-beta (A beta) appears critical to Alzheimer's disease. To clarify p ossible mechanisms of A beta action, we have quantified A beta-induced gene expression in vitro by using A beta-treated primary cortical neuronal cult ures and in vivo by using mice transgenic for the A beta precursor (A beta P). Here, we report that aggregated, but not nonaggregated, A beta increase s the level of the mRNAs encoding tissue plasminogen activator (tPA) and ur okinase-type plasminogen activator (uPA). Moreover, tPA and uPA were also u pregulated in aged A beta P overexpressing mice. Because others have report ed that A beta aggregates can substitute for fibrin aggregates in activatin g tPA post-translationally, the result of tPA induction by A beta would be cleavage of plasminogen to the active protease plasmin. To gain insights in to the possible actions of plasmin, we evaluated the hypotheses that tPA an d plasmin may mediate A beta in vitro toxicity or, alternatively, that plas min activation may lead to A beta degradation. In evaluating these conflict ing hypotheses, we found that purified plasmin degrades A beta with physiol ogically relevant efficiency, i.e., similar to 1/10th the rate of plasmin o n fibrin. Mass spectral analyses show that plasmin cleaves A beta at multip le sites. Electron microscopy confirms indirect assays suggesting that plas min degrades A beta fibrils. Moreover, exogenously added plasmin blocks A b eta neurotoxicity. In summation, we interpret these results as consistent w ith the possibility that the plasmin pathway is induced by aggregated A bet a, which can lead to A beta degradation and inhibition of A beta actions.