Abeta(1-40)-induced secretion of matrix metalloproteinase-9 results in sAPPalpha release by association with cell surface APP.
To understand matrix metalloproteinase-9 (MMP-9) involvement in Alzheimer's disease, we examined mechanisms mediating increased expression of MMP-9 in the presence of Abeta(1-40) and the role of MMP-9 on amyloid precursor protein (APP) processing. Up-regulation of MMP-9 expressed by SK-N-SH cells in the presence of Abeta(1-40) was mediated by alpha(3)beta(1) and alpha(2)beta(1) integrin receptors. Overexpression of MMP-9 or treatment of HEK/APP695 cells with activated recombinant MMP-9 resulted in enhanced secretion of soluble APP (sAPPalpha), a product of alpha-secretase cleavage, and reduction of Abeta release. MMP-9 effect was enhanced by phorbol 12-mysistrate-13-acetate (PMA), an alpha-secretase activator and inhibited by EDTA or SB-3CT, an MMP-9 inhibitor. Additionally, immunoprecipitation and confocal microscopy demonstrated that MMP-9 and APP695 were associated on the cell surface. These results indicate that Abeta peptide increases MMP-9 secretion through integrins; MMP-9 then directly processes cell surface APP695 with an alpha-secretase like activity, substantially reducing the levels of secreted Abeta peptide.
Talamagas
Argiris A
AA
Institute of Biology, National Centre for Scientific Research "Demokritos", 15310 Agia Paraskevi, Athens, Greece.
Efthimiopoulos
Spiros
S
Tsilibary
Effie C
EC
Figueiredo-Pereira
Maria E
ME
Tzinia
Athina K
AK
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011994:Recombinant Proteins; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D020780:Matrix Metalloproteinase 9