RT Journal Article
SR Electronic
T1 The Plasmin System Is Induced by and Degrades Amyloid-β Aggregates
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3937
OP 3946
DO 10.1523/JNEUROSCI.20-11-03937.2000
VO 20
IS 11
A1 H. Michael Tucker
A1 Muthoni Kihiko
A1 Joseph N. Caldwell
A1 Sarah Wright
A1 Takeshi Kawarabayashi
A1 Douglas Price
A1 Donald Walker
A1 Stephen Scheff
A1 Joseph P. McGillis
A1 Russell E. Rydel
A1 Steven Estus
YR 2000
UL http://www.jneurosci.org/content/20/11/3937.abstract
AB Amyloid-β (Aβ) appears critical to Alzheimer's disease. To clarify possible mechanisms of Aβ action, we have quantified Aβ-induced gene expression in vitro by using Aβ-treated primary cortical neuronal cultures and in vivo by using mice transgenic for the Aβ precursor (AβP). Here, we report that aggregated, but not nonaggregated, Aβ increases the level of the mRNAs encoding tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Moreover, tPA and uPA were also upregulated in aged AβP overexpressing mice. Because others have reported that Aβ aggregates can substitute for fibrin aggregates in activating tPA post-translationally, the result of tPAinduction by Aβ would be cleavage of plasminogen to the active protease plasmin. To gain insights into the possible actions of plasmin, we evaluated the hypotheses that tPA and plasmin may mediate Aβ in vitro toxicity or, alternatively, that plasmin activation may lead to Aβ degradation. In evaluating these conflicting hypotheses, we found that purified plasmin degrades Aβ with physiologically relevant efficiency, i.e., ∼1/10th the rate of plasmin on fibrin. Mass spectral analyses show that plasmin cleaves Aβ at multiple sites. Electron microscopy confirms indirect assays suggesting that plasmin degrades Aβ fibrils. Moreover, exogenously added plasmin blocks Aβ neurotoxicity. In summation, we interpret these results as consistent with the possibility that the plasmin pathway is induced by aggregated Aβ, which can lead to Aβ degradation and inhibition of Aβ actions.