Increased expression of the urokinase plasminogen-activator receptor in amyloid beta peptide-treated human brain microglia and in AD brains.
The urokinase plasminogen-activator receptor (uPAR) is involved in many processes in inflammation including the migration of inflammatory-associated cells to sites of tissue damage. This receptor, also designated as CD87, is induced in response to a range of stimuli and is a marker of macrophage activation. Its role in inflammatory responses of microglia in Alzheimer's disease (AD) has not been previously investigated. In this study we demonstrate that uPAR mRNA and protein expression is induced following incubation of human post-mortem brain-derived microglia with fibrillar amyloid beta (Abeta) peptide. This response was stronger with Abeta peptide than with other tested pro-inflammatory agents. Induction of uPAR surface expression by microglia was inhibited by the antioxidant N-acetyl-cysteine, indicating that this gene may be induced as a result of oxidative stress-related mechanisms. The significance of these findings to AD was investigated. UPAR protein levels were significantly increased in human brain tissues from the hippocampus, superior frontal gyrus and inferior temporal gyrus of AD cases compared with similar tissues from non-demented cases. Increased uPAR expression was not demonstrated in AD cerebellum. Finally, increased uPAR immunoreactivity was demonstrated in activated microglia in AD brain samples using two different antibodies to uPAR. These results provide a connection between the induction of oxidative stress in AD and microglial activation, and establish a possible involvement of uPAR in AD pathogenesis.
Walker
Douglas G
DG
Civin Laboratory of Neuropathology, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. dgwalker@altavista.com
Lue
Lih-Fen
LF
Beach
Thomas G
TG
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008297:Male; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D018384:Oxidative Stress / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction / Q000502:physiology
D016229:Amyloid beta-Peptides; D005609:Free Radicals; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator