Transglutaminase 2 silencing reduced the beta-amyloid-effects on the activation of human THP-1 cells

The aberrant expression and activation of transglutaminase 2 (TG2), the ubiquitous enzyme which catalyzes calcium-dependent protein cross-linking reactions, has been reported in many inflammatory diseases. Chronic inflammation, mediated by prolonged activation of brain-resident immunocompetent cells, appears to be involved in the pathogenesis of several age-related diseases, such as Alzheimer’s disease. Given that increased TG2 expression has been observed in AD brains, this study was aimed to characterize the role of TG2 in THP-1 monocytes stimulated with amyloid-beta (Abeta). Abeta1–42 treatment dose-dependently increased TG2 expression in THP-1 cells. In particular, a fivefold up-regulation of TG2, compared with control cells, was observed in the presence of 0.5 µM Abeta1–42. At the same concentration, Abeta1–42 was able to promote monocyte maturation as suggested by increased expression of the cell surface antigen CD14 as well as the adhesion-promoting factor fibronectin. The stimulation of THP-1 cells with Abeta1–42 also led to a significant up-regulation of tumor necrosis factor alpha (TNF-alpha) and matrix metalloproteinase 9 (MMP-9). Interestingly, THP-1 cell transfection with small interfering RNA directed against TG2 was able to reduce Abeta1–42 increased levels of all the examined markers of monocyte maturation (CD14, fibronectin), and activation (TNF-alpha, MMP-9). These results indicate that TG2 up-regulation is required for the functional THP-1 monocyte activation induced by Abeta1–42. This work suggests that TG2 inhibition may represent a therapeutic target to ameliorate the inflammation and progression in Alzheimer’s disease.