The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration.
Accumulation of the amyloid-beta (Abeta) peptide depends on both its generation and clearance. To better define clearance pathways, we have evaluated the role of the tissue plasminogen activator (tPA)-plasmin system in Abeta degradation in vivo. In two different mouse models of Alzheimer's disease, chronically elevated Abeta peptide in the brain correlates with the upregulation of plasminogen activator inhibitor-1 (PAI-1) and inhibition of the tPA-plasmin system. In addition, Abeta injected into the hippocampus of mice lacking either tPA or plasminogen persists, inducing PAI-1 expression and causing activation of microglial cells and neuronal damage. Conversely, Abeta injected into wild-type mice is rapidly cleared and does not cause neuronal degeneration. Thus, the tPA-plasmin proteolytic cascade aids in the clearance of Abeta, and reduced activity of this system may contribute to the progression of Alzheimer's disease.
Melchor
Jerry P
JP
Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York 10021, USA.
Pawlak
Robert
R
Strickland
Sidney
S
D000544:Alzheimer Disease / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D010958:Plasminogen / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; C078592:amyloid beta-protein (1-40); D010958:Plasminogen; D010959:Tissue Plasminogen Activator