The inhibitory effects of bile acids on catalytic and non-catalytic functions of acetylcholinesterase as a therapeutic target in Alzheimer’s disease

Abstract

Acetylcholine is a fast-acting neurotransmitter in synapses and neuromuscular junctions that is decreased in Alzheimer's disease (AD) by hyper‑activation of acetylcholinesterase (AChE), which leads to progressive loss of memory and neurobehavioral abnormalities. Therefore, AChE inhibitors have therapeutic potential in AD that could include natural compounds such as bile acids. Bile acids, as potent molecules, could improve some types of neurodegenerative diseases via antioxidant effects and other unknown mechanisms. The aim of this study was to investigate beneficial effects of bile acids on AChE catalytic and non‑catalytic functions, amyloid plaque deposit and memory in a rat model of AD. The effects of sodium deoxycholate and cholic acid on AChE activity were assessed by in vitro assay. Then, the bile acids' potential therapeutic effects were investigated on nucleus basalis of Meynert lesioned rats using behavioral evaluation, biochemical tests and histological methods. Molecular docking simulation was also implemented to investigate the possible interaction between bile acids and AChE. According to the in vitro and in vivo results, sodium deoxycholate could efficiently inhibit the catalytic function of the enzyme by interacting with the catalytic site, while cholic acid interacted with the peripheral anionic site and inhibited chaperone activity of the enzyme that led to the reduced amyloid plaque deposition. The co‑administration of cholic acid and sodium deoxycholate showed these compounds are able to simultaneously inhibit the catalytic and non‑catalytic functions of the enzyme. This study clarifies the roles of natural bile acids in the nervous system and in AChE function through multiple experimental and simulation methods.