The plasmin system is induced by and degrades amyloid-beta aggregates：（血纤维蛋白溶酶系统是由和降解淀粉样β蛋白总量）.pdfVIP

The Journal of Neuroscience, June 1, 2000, 20(11):3937–3946 The Plasmin System Is Induced by and Degrades Amyloid- Aggregates H. Michael Tucker,1 Muthoni Kihiko,1 Joseph N. Caldwell,1 Sarah Wright,5 Takeshi Kawarabayashi,4 Douglas Price,2 Donald Walker,5 Stephen Scheff,2 Joseph P. McGillis,3 Russell E. Rydel,5 and Steven Estus1 1Department of Physiology, 2Department of Anatomy and Neurobiology, Sanders-Brown Center on Aging, and 3Department of Microbiology and Immunology, University of Kentucky, Lexington, Kentucky 40536, 4Mayo Clinic, Jacksonville, Florida 32224, and 5Elan Pharmaceuticals, Inc., South San Francisco, California 94080 Amyloid- (A) appears critical to Alzheimer’s disease. To clar- that tPA and plasmin may mediate A in vitro toxicity or, alter- ify possible mechanisms of A action, we have quantified natively, that plasmin activation may lead to A degradation. In A-induced gene expression in vitro by using A-treated pri- evaluating these conflicting hypotheses, we found that purified mary cortical neuronal cultures and in vivo by using mice plasmin degrades A with physiologically relevant efficiency, transgenic for the A precursor (AP). Here, we report that i.e., 1/10th the rate of plasmin on fibrin. Mass spectral anal- aggregated, but not nonaggregated, A increases the level of yses show that plasmin cleaves A at multiple sites. Electron the mRNAs encoding tissue plasminogen activator (tPA) and microscopy confirms indirect assays suggesting that plasmin urokinase-type plasminogen activator (uPA). Moreover, tPA and degrades A fibrils. Moreover, exogenously added plasmin uPA were also upregulated in aged AP overexpressing mice.