Urokinase-type plasminogen activator inhibits amyloid-beta neurotoxicity and fibrillogenesis via plasminogen.
Amyloid-beta (Abeta) appears central to Alzheimer's disease (AD), aggregates spontaneously, and is neurotoxic to neurons in vitro. Recently, several groups reported a familial AD locus on chromosome 10. Here, we note that urokinase-type plasminogen activator (uPA) is located within this locus. Previously, we reported that uPA and its functional homolog, tissue-type plasminogen activator, are induced by Abeta treatment of neurons in vitro as well as in a mouse model of Abeta accumulation in vivo. Moreover, the target of plasminogen activators, plasmin, degraded nonaggregated and aggregated Abeta and modulated Abeta toxicity and deposition. Here, we have evaluated the effects of uPA and plasminogen on Abeta fibril formation and neurotoxicity. We report that the combination of uPA and plasminogen, but neither alone, inhibits Abeta toxicity, reduces Abeta deposition in vitro, and inhibits Abeta fibrillogenesis. We interpret these observations as suggesting that uPA represents a possible candidate gene for the chromosome 10 familial AD locus.
Tucker
H Michael
HM
Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
Kihiko-Ehmann
Muthoni
M
Estus
Steven
S
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D004359:Drug Therapy, Combination; D005455:Fluorescent Antibody Technique; D006801:Humans; D046911:Macromolecular Substances; D008854:Microscopy, Electron; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D010958:Plasminogen / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator