Accumulating evidence suggests parasympathetic dysfunction and elevated inflammation as underlying processes in multiple peripheral and neurological diseases. Acetylcholine, the main parasympathetic neurotransmitter and inflammation regulator, is hydrolyzed by the two closely homologous enzymes, acetylcholinesterase and butyrylcholinesterase (AChE and BChE, respectively), which are also expressed in the serum. Here, we consider the potential value of both enzymes as possible biomarkers in diseases associated with parasympathetic malfunctioning. We cover the modulations of cholinesterase activities in inflammation-related events as well as by cholinesterase-targeted microRNAs. We further discuss epigenetic control over cholinesterase gene expression and the impact of single-nucleotide polymorphisms on the corresponding physiological and pathological processes. In particular, we focus on measurements of circulation cholinesterases as a readily quantifiable readout for changes in the sympathetic/parasympathetic balance and the implications of changes in this readout in health and disease. Taken together, this cumulative know-how calls for expanding the use of cholinesterase activity measurements for both basic research and as a clinical assessment tool.

The metabolic syndrome (MetS) is a risk factor for type 2 diabetes mellitus (T2DM). However, the mechanisms underlying the transition from MetS to T2DM are unknown. Our goal was to study the potential contribution of butyrylcholinesterase (BChE) to this process. We first determined the hydrolytic activity of BChE in serum from MetS, T2DM and healthy individuals. The ‘Kalow’ variant of BChE (BChE-K), which has been proposed to be a risk factor for T2DM, was genotyped in the last two groups. Our results show that in MetS patients serum BChE activity is elevated compared to T2DM patients and healthy controls (P < 0.001). The BChE-K genotype showed similar prevalence in T2DM and healthy individuals, excluding this genotype as a risk factor for T2DM. However, the activity differences remained unexplained. Previous results from our laboratory have shown BChE to attenuate the formation of β-amyloid fibrils, and protect cultured neurons from their cytotoxicity. Therefore, we next studied the in vitro interactions between recombinant human butyrylcholinesterase and amylin by surface plasmon resonance, Thioflavine T fluorescence assay and cross-linking, and used cultured pancreatic β cells to test protection by BChE from amylin cytotoxicity. We demonstrate that BChE interacts with amylin through its core domain and efficiently attenuates both amylin fibril and oligomer formation. Furthermore, application of BChE to cultured β cells protects them from amylin cytotoxicity. Taken together, our results suggest that MetS-associated BChE increases could protect pancreatic β-cells in vivo by decreasing the formation of toxic amylin oligomers.

Obesity-related AChE resistance phenotype may be reversed following LSG and correlates with metabolic outcomes. Further long-term studies will be needed to validate and evaluate the beneficial effect of AChE reduction post bariatric surgery.

Background specific heart rate parameters notably associate with variable risks of cardiovascular disease and mortal-ity, however, to date there are no readily available blood tests associated with these parameters. Because of the estab-lished parasympathetic contributions towards cardiac regulation, we challenged the working hypothesis that serum acetylcholinesterase (AChE) activity is involved. Methods A total of 403 Healthy men and women were included in the study and underwent treadmill exercise testing. Prior to exercise testing the subject’s serum AChE activity levels were assessed by measuring rates of acetylthiocholine hydrolysis. Results In male subjects AChE activity was positively cor-related to resting heart rate (r = 0.210, p = 0.001). Complementing this observation, AChE activity was negatively correlated to the exercise-induced heart rate increase (r = –0.181, p = 0.005) and to heart rate recovery at 1, 2 and 5 minutes following cessation of exercise (r = –0.150, p = 0.022; r = –0.157, p = 0.016; r = –0.176, p = 0.008 respec-tively). This indicated that lower than average AChE activities, which presumably reflect increased peripheral ACh levels, might be correlated to favorable heart rate parameters. Similar observations were made in female subjects, ex-cept for lack of correlation to their resting heart rate. Additionally, we observed that we were able to stratify subjects into two groups of significantly different AChE activity (p = 0.001) based on a cut point of heart rate recovery below 20 beats one minute after cessation of exercise. Conclusion In asymptomatic individuals lower than average AChE activity is associated with favorable indices of exercise-inducible heart rate increase as well as heart rate recovery. Future studies will be needed to evaluate the added prognostic significance gained by implementing this marker into routine practice