期刊
NEUROBIOLOGY OF DISEASE
卷 28, 期 3, 页码 304-315出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2007.07.016
关键词
MMP-9; amyloid precursor protein; secretase; integrin; Alzheimer; amyloid beta peptide
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 A beta (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 (sAPP alpha), a product of alpha-secretase cleavage, and reduction of A beta 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 A beta 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 A beta peptide. (C) 2007 Elsevier Inc. All rights reserved.
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