Changes in arginine metabolism in advanced Alzheimer's patients: Experimental and theoretical analyses

Limited data obtained in studies conducted in recent years suggest that changes in arginine metabolism may be associated with the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanisms of this pathway's effects on the disease are not clear and there are conflicting data. Therefore, in this study, we aimed to determine the levels of l -arginine and its important metabolites and enzymes involved in the pathway in advanced AD patients to examine the change in l -arginine metabolism as inclusively as possible. Serum and plasma samples were obtained from 51 patients diagnosed with advanced AD and 30 volunteer controls. Arginase, Ornithine Decarboxylase (ODC), Arginine Decarboxylase (ADC), and Agmatinase levels in serum samples were determined by enzyme-linked immunosorbent assay (ELISA) and, l -arginine, Ornithine and nitric oxide (NO) levels were determined by colorimetric method. Agmatine levels were measured by high-performance liquid chromatography in the plasma samples of the study groups. Furthermore, in silico molecular docking studies were performed to get preliminary knowledge about the binding interactions of the agmatine with various targets such as AChE, butyrylcholinesterase (BuChE), BACE-1 and tau protein kinase 1 which play an important role in AD pathogenesis. Agmatine and l -arginine levels were found to be significantly lower in the patient group than in the control group. Milder but not statistically significant reductions were observed in all other parameters we measured involved in l -arginine metabolism. Furthermore, NO levels were found to be significantly lower in men with advanced AD patients than in control men. It has been analyzed that agmatine ligand interacts effectively with the studied proteins which play an important role in AD pathogenesis; these interactions were significant and, based on the docking score, occurred in the following order: butyrylcholinesterase (PDB id: 1P0I) > Human acetylcholinesterase > Human tau-protein kinase I. In conclusion, in advanced AD patients, the activity of the l -arginine pathway decreased in general, especially agmatine formation, and this may be due to the decrease in l -arginine levels. Therefore, arginine de novo synthesis may be decreased in advanced AD patients. Furthermore, according to the MolDock binding score, agmatine ligand has a high binding affinity for proteins involved in AD management and/or pathogenesis. Therefore, agmatine may play a role in the pathogenesis of AD by inhibiting the activity of these proteins. However, additional comprehensive studies are needed to clarify these thoughts.