Effect of natural antioxidants on tissue transglutaminase overexpression induced by amyloid-?: biological, molecular and computational studies

Alzhèimer Disease (AD), one of the most common neurodegenerative diseases, is characterized by progressive neuronal loss and accumulation of proteins, including Amyloid-beta (A?), a neurotoxic protein. It is known that tissue transglutaminase (TG2), an ubiquitary calcium-dependent protein, is involved in protein aggregation in AD. Previous our studies showed that A?(1-42) and its fragments A?(25-35) and A?(35-25) induced an overexpression of TG2 and its isoforms on Olfactory Ensheathing Cells (OECs), a glial population of the olfactory system that express neural stem cell markers, including Nestin. In the last years growing attention rose on neuronutraceutics and their effect on mental health. Among these molecules, we focused our research on indicaxanthin, and astaxanthin, natural compounds that were able to cross the blood-brain barrier. In this study, the effect of indicaxanthin or astaxanthin pre-treatment on TG2 and its isoform expression levels exposed to A?(1-42) or by A?(25-35) or A?(35-25) on OECs was assessed. Furthermore, we evaluated thei effect on the expression levels of Vimentin and Glial Fibrillary Acid Protein (GFAP). The percentage of cell viability and the apoptotic pathway activation were also evaluated. Since Nestin, a marker of neural precursors, is co-expressed in pluripotent stem cells with cyclin D1, a marker of cellular proliferation, the effect of indicaxanthin and astaxanthin pre-treatment on their expression levels was also tested. In addition, the production of total reactive oxygen species (ROS) and superoxide anion (O2-.), were assessed. In parallel, docking studies were performed to obtain informations relative to the interaction between the indicaxanthin or astaxanthin and TG2. We found that indicaxanthin or astaxanthin pre-treatment was able to reduce TG2 overexpression and its isoforms, decreasing total ROS and O2-.production and GFAP and Vimentin expression levels. In addition, they inhibited apoptotic pathway activation and induced an increase in the Nestin and cyclin D1 expression levels. Docking results showing that indicaxanthin and astaxanthin were able to prevent the TG2 change conformation induced by A?. Our data demonstrated that indicaxanthin or astaxanthin pre-treatment stimulated OECs self-renewal through the reparative activity played by TG2. Therefore, indicaxanthin and astaxanthin might represent an innovative mechanism to contrast TG2 overexpression in AD.