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

Abstract

Prior studies using rat primary hippocampal cultures indicated induction of matrix metalloproteinases (MMPs) in response to β-amyloid (Aβ). Hence, it was of interest to determine whether MMP activity in a human cell line is influenced by Aβ. Aβ, but not interleukin-1β (IL-1β) 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 Aβ-induced active MMP-2 in U87 cells. The induction of MMP-3 by cytokines, but not by Aβ, suggests that the effect of Aβ on MMP-2 is selective. Although Aβ stimulated tissue inhibitor of metalloproteinase-1 (TIMP-1), there was no obvious effect of Aβ on TIMP-2 production in U87 cells. These results demonstrate that Aβ 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 Aβ or act on ECM components critical in neuronal survival mechanisms and possibly play a role in Alzheimer's disease (AD) neuropathology.