Abstract
Accumulation of the amyloid-beta (Abeta) peptide in the brain is a crucial factor in the development of Alzheimer disease. Expression of transforming growth factor-beta1 (TGF-beta1), an immunosuppressive cytokine, has been associated in vivo with Abeta accumulation in transgenic mice and recently with Abeta clearance by activated microglia, suggesting its deleterious and beneficial effects in neuronal cells. In this study, we demonstrated that TGF-beta1 stimulated the production of matrix metalloproteinase-2 (MMP-2) in a time- and dose-dependent manner in a human monocytic THP-1 cell line. Notably, we found that Abeta1-42 consistently inhibited the TGF-beta1-induced production of MMP-2, the endogenous gene containing Smad response elements, whereas the reverse peptide, Abeta42-1, evidenced little effect. Additionally, Abeta1-42 reduced TGF-beta1-induced increase in plasminogen activator inhibitor-1 (PAI-1). This inhibitory effect of Abeta1-42 was also seen in human astroglial T98G cell line. Furthermore, Abeta1-42 significantly induced the expression of Smad7, which appears in turn to mediate the Abeta suppression of the TGF-beta1-induced MMP-2 production. Indeed, Smad7 overexpression mimicked the inhibitory effect of Abeta1-42 on TGF-beta1-induced MMP-2 production. Importantly, Abeta1-42 markedly suppressed the transactivation of the transfected reporter construct, p3TP-Lux, which contains TGF-beta1-inducible Smad response elements. This was concomitant with a decreased MMP-2 production in TGF-beta1-treated cells. Inhibition of cellular Smad7 levels via the small interference RNA method significantly ameliorated the Abeta1-42-mediated suppression of TGF-beta1-inducible transcription reporter activity, thereby restoring MMP-2 induction, whereas Smad7 transfection down-regulated TGF-beta1-inducible transcription reporter activity. Collectively, these data suggest that Abeta1-42 may play an important role in the negative regulation of TGF-beta1-induced MMP-2 production via Smad7 expression.
Highlights
Alzheimer disease (AD)1 is a progressive neurodegenerative disorder, which is characterized by the loss of higher cognitive functions
To assess the potential involvement of matrix metalloproteinase-2 (MMP-2) in the A modulation of transforming growth factor-1 (TGF-1) function, we examined TGF1-induced matrix metalloproteinases (MMPs)-2 production in monocytic THP-1 cells because MMP-2 contains TGF--inducible Smad-binding elements (SBEs) domains in its promoter regions [17, 26]
A1– 42 Inhibits Transcriptional Activation of TGF-1-inducible SBE-containing Promoters in THP-1 Cells—Given that SBEs are present in the promoter regions of MMP-2 [26], we further examined the effects of A1– 42 on the well characterized TGF-1-inducible SBE-containing promoter-reporter construct, p3TP-Lux [34, 35], which was utilized in THP-1 cells to examine the induction of transcriptional activity by TGF-1
Summary
Alzheimer disease (AD)1 is a progressive neurodegenerative disorder, which is characterized by the loss of higher cognitive functions. A1– 42 treatment of THP-1 cells resulted in a decrease of TGF-1-induced MMP-2 activity over the level seen in TGF-1-treated cells, whereas the reverse peptide, A42–1, elicited only minimal effects under the same experimental conditions (Fig. 3). Consistent with the rescue of the TGF-1-mediated MMP-2 activity, the A1– 42 suppression of TGF-1-inducible transcriptional reporter activity was restored in the Smad7-siRNA-treated cells (Fig. 8, C).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
