Amyloid Beta Exposure on Olfactory Ensheathing Cells Induces Different Expression Pattern of Tissue Transglutaminase and Its Isoforms: Modulatory Effect of Indicaxanthin

Abstract

Abstract Background Alzhèimer Disease (AD) is characterized by intracellular and extracellular protein aggregates in the brain, including amyloid-beta (Aβ). Aβ is a substrate for tissue transglutaminase (TG2), an ubiquitarian calcium-dependent protein that induces Aβ oligomerization and aggregation. We assessed the effect of full native peptide of Aβ(1–42), the fragments (25–35 and 35–25) on TG2 expression levels and its isoforms (Long and Short) on Olfactory Ensheathing Cells (OECs). The levels of cytoskeletal proteins, Vimentin and Glial Fibrillary Acid Protein (GFAP), were also studied. The effect of the pre-treatment with Indicaxanthin on cell viability, total Reactive Oxygen Species (ROS), superoxide anion (O2−) and apoptotic pathway activation was assessed. Since Nestin is co-expressed in pluripotent stem cells with cyclin D1, their levels were evaluated. Methods Mouse primary OECs were exposed to 10 µM Aβ(1–42) or Aβ(25–35) or Aβ(35–25) for 24 h both in the absence and in the presence of Indicaxanthin. TG2 and its isoforms were evaluated through Confocal Laser Scanning Microscopy and Western Blot analysis. Data were statistically analysed using one-way analysis of variance followed by post hoc Holm–Sidak. Results Our findings highlight that OEC exposure to Aβ(1–42) and its fragments induced an increase of TG2 levels and the different expression pattern of its isoforms. Indicaxanthin pre-treatment reduced TG2 over-expression differently modulating its isoforms, following Aβ exposure of the cells. It was also able to prevent total ROS and O2−production, to reduce GFAP and Vimentin levels, inhibiting apoptotic pathway activation. It also leaded to an increase of Nestin and cyclin D1 expression levels. Conclusions Our results show that Aβ exposure on OECs induces an increase of TG2 levels and a different expression pattern of its isoforms and that Indicaxanthin pre-treatment stimulates OEC self-renewal through the reparative activity played by TG2. They also suggest that Aβ in OECs, both in the absence and in the presence of Indicaxanthin, might differently induce the transition of TG2 between “closed” and “open” conformation, providing a new mechanism involved in the signal pathways activated by the protein in Aβ injury important for neural regeneration of AD.