Tissue plasminogen activator requires plasminogen to modulate amyloid-beta neurotoxicity and deposition.
Tissue plasminogen (plgn) activator (tPA) modulates neuronal death in models of stroke, excitotoxicity, and oxidative stress. Amyloid-beta (Abeta) appears central to Alzheimer's disease and is neurotoxic to neurons in vitro. Here, we evaluate tPA effects on Abeta toxicity. We report that tPA alone had no effect on Abeta toxicity. However, in combination with plgn, tPA reduced Abeta toxicity in a robust fashion. Moreover, the combined tPA and plgn treatment markedly inhibited Abeta accumulation. The addition of phenylmethylsulfonyl fluoride, a serine protease inhibitor, to a sample of tPA, plgn, and Abeta resulted in a marked reduction of Abeta degradation. We interpret the actions of tPA and plgn within the context of the ability of plasmin to degrade Abeta.
Tucker
H M
HM
Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA. mtucker@pop.uky.edu
Kihiko-Ehmann
M
M
Wright
S
S
Rydel
R E
RE
Estus
S
S
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity* / Q000648:ultrastructure; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D008854:Microscopy, Electron; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D010958:Plasminogen / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D010959:Tissue Plasminogen Activator / Q000378:metabolism* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010664:Phenylmethylsulfonyl Fluoride; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin