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). Hence, it was of interest to determine whether MMP activity in a human cell line is influenced by A beta. A beta, but not interleukin-1beta (IL-1beta) or lipopolysaccharide (LPS), stimulated an active form of MMP-2 in human U87 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 well as immunoblotting, suggest that the lower molecular weight, gelatin-degrading activity was an activated form of MMP-2. Furthermore, it was demonstrated that a synthetic furin convertase inhibitor, decanoyl-Arg-Val-Lys-Arg-chloromethylketone, decreased the production of A beta-induced active MMP-2 in U87 cells. The induction of MMP-3 by cytokines, but not by A beta, suggests that the effect of A beta on MMP-2 is selective. Although A beta stimulated tissue inhibitor of metalloproteinase-1 (TIMP-1), there was no obvious effect 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 expression 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 and possibly play a role in Alzheimer's disease (AD) neuropathology.
Deb
S
S
Department of Pharmacology and Therapeutics, University of South Florida, College of Medicine, Tampa 33612-4799, USA.
Zhang
J W
JW
Gottschall
P E
PE
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045683:Furin; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011233:Precipitin Tests; D013381:Subtilisins / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010446:Peptide Fragments; D013381:Subtilisins; D045683:Furin; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2