Activated isoforms of MMP-2 are induced in U87 human glioma cells in response to beta-amyloid peptide

Prior studies using rat primary hippocampal cultures indicated induction of matrix metalloproteinases (MMPs) in response to beta-amyloid (A beta). Hen ce, it was of interest to determine whether MMP activity in a human cell li ne is influenced by A beta, A beta, but not interleukin-1 beta (IL-1 beta) or lipopolysaccharide (LPS), stimulated an active form of MMP-2 in human US 7 glioblastoma cells, as well as increased the expression of the well-known activator of MMP-2, membrane-type (MT)-MMP. Activation experiments carried out with amino phenyl mercuric acetate (APMA), immunoprecipitation, as wel l as immunoblotting, suggest that the lower molecular weight, gelatin-degra ding activity was an activated form of MMP-2. Furthermore, it was demonstra ted that a synthetic furin convertase inhibitor, decanoyl-Arg-Val-Lys-Arg-c hloromethylketone, decreased the production of A beta-induced active MMP-2 in U87 cells. The induction of MMP-3 by cytokines, but not by AP, suggests that the effect of A beta on MMP-2 is selective. Although A beta stimulated tissue inhibitor of metalloproteinase-l (TIMP-1), there was no obvious eff ect of A beta on TIMP-2 production in U87 cells. These results demonstrate that A beta induces an active form of MMP-2 likely by increasing the expres sion of MT-MMP in a human glioblastoma cell line, Active MMP-2 may degrade A beta or act on ECM components critical in neuronal survival mechanisms an d possibly play a role in Alzheimer's disease (AD) neuropathology. (C) 1999 Wiley-Liss,Inc.