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 Aβ(1-40) was mediated by α3β1 and α2β1 integrin receptors. Overexpression of MMP-9 or treatment of HEK/APP695 cells with activated recombinant MMP-9 resulted in enhanced secretion of soluble APP (sAPPα), a product of α-secretase cleavage, and reduction of Aβ release. MMP-9 effect was enhanced by phorbol 12-mysistrate-13-acetate (PMA), an α-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 Aβ peptide increases MMP-9 secretion through integrins; MMP-9 then directly processes cell surface APP695 with an α-secretase like activity, substantially reducing the levels of secreted Aβ peptide.
Bibliographical noteFunding Information:
The authors are indebted to Dr. Rafael Fridman (Department of Pathology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan, USA) for providing the pcDNA3.1Myc 6His/pro-MMP-9 construct and P. Handris for their expert technical assistance in performing confocal microscopy. This research was funded by NCSR Demokritos and donations from “TRIAS CO”/N. Kounelis, “HALYPS CO”/A. Noulis, “BIOTREK A.B.E.E.”/I. Louis. Part of this research was also funded by grants from the Ministry of Education (Pythagoras I and II), the University of Athens (Kapodistrias) and Embirikion foundation.
- Amyloid beta peptide
- Amyloid precursor protein