Abstract
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.
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References
Adabag AS et al (2008) Relation of heart rate parameters during exercise test to sudden death and all-cause mortality in asymptomatic men. Am J Cardiol 101(10):1437–1443
Alcantara VM et al (2002) Butyrylcholinesterase activity and risk factors for coronary artery disease. Scand J Clin Lab Invest 62(5):399–404
Alkalay A et al (2013) Plasma acetylcholinesterase activity correlates with intracerebral beta-amyloid load. Curr Alzheimer Res 10(1):48–56
Alvarez GE et al (2002) Sympathetic neural activation in visceral obesity. Circulation 106(20):2533–2536
Arena R et al (2006) Prognostic value of heart rate recovery in patients with heart failure. Am Heart J 151(4):851.e7–851.e13
Bai A, Guo Y, Lu N (2007) The effect of the cholinergic anti-inflammatory pathway on experimental colitis. Scand J Immunol 66(5):538–545
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233
Ben Assayag E et al (2010) Serum cholinesterase activities distinguish between stroke patients and controls and predict 12-month mortality. Mol Med 16(7–8):278–286
Benmoyal-Segal L et al (2005) Acetylcholinesterase/paraoxonase interactions increase the risk of insecticide-induced Parkinson’s disease. FASEB J 19(3):452–454
Berson A et al (2012) Cholinergic-associated loss of hnRNP-A/B in Alzheimer’s disease impairs cortical splicing and cognitive function in mice. EMBO Mol Med 4(8):730–742
Bhuiyan MB, Murad F, Fant ME (2006) The placental cholinergic system: localization to the cytotrophoblast and modulation of nitric oxide. Cell Commun Signal 4:4
Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95
Birikh KR et al (2003) Interaction of “readthrough” acetylcholinesterase with RACK1 and PKCbeta II correlates with intensified fear-induced conflict behavior. Proc Natl Acad Sci U S A 100(1):283–288
Borovikova LV et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405(6785):458–462
Calabresi P et al (2006) A convergent model for cognitive dysfunctions in Parkinson’s disease: the critical dopamine–acetylcholine synaptic balance. Lancet Neurol 5(11):974–983
Calderon-Margalit R et al (2006) Butyrylcholinesterase activity, cardiovascular risk factors, and mortality in middle-aged and elderly men and women in Jerusalem. Clin Chem 52(5):845–852
Cole CR et al (1999) Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 341(18):1351–1357
Conner JM et al (2003) Lesions of the basal forebrain cholinergic system impair task acquisition and abolish cortical plasticity associated with motor skill learning. Neuron 38(5):819–829
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 285(19):2486–2497
Ford ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287(3):356–359
Frank R, Hargreaves R (2003) Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2(7):566–580
Ganguli SC et al (2007) A comparison of autonomic function in patients with inflammatory bowel disease and in healthy controls. Neurogastroenterol Motil 19(12):961–967
Ghia JE et al (2006) The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131(4):1122–1130
Giacobini E (2003) Cholinergic function and Alzheimer’s disease. Int J Geriatr Psychiatry 18(Suppl 1):S1–S5
Goliasch G et al (2012a) Routinely available biomarkers improve prediction of long-term mortality in stable coronary artery disease: the Vienna and Ludwigshafen Coronary Artery Disease (VILCAD) risk score. Eur Heart J 33(18):2282–2289
Goliasch G et al (2012b) Butyrylcholinesterase activity predicts long-term survival in patients with coronary artery disease. Clin Chem 58(6):1055–1058
Greenwood JP, Stoker JB, Mary DA (1999) Single-unit sympathetic discharge: quantitative assessment in human hypertensive disease. Circulation 100(12):1305–1310
Guest PC, Gottschalk MG, Bahn S (2013) Proteomics: improving biomarker translation to modern medicine? Genome Med 5(2):17
Hanin G, Soreq H (2011) Cholinesterase-targeting microRNAs identified in silico affect specific biological processes. Front Mol Neurosci 4:28
Honda K et al (2013) Proteomic approaches to the discovery of cancer biomarkers for early detection and personalized medicine. Jpn J Clin Oncol 43(2):103–109
Humpel C (2011) Identifying and validating biomarkers for Alzheimer’s disease. Trends Biotechnol 29(1):26–32
Jouven X et al (2005) Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med 352(19):1951–1958
Kaufer D et al (1998) Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature 393(6683):373–377
Kawashima K, Fujii T (2000) Extraneuronal cholinergic system in lymphocytes. Pharmacol Ther 86(1):29–48
Kawashima K, Fujii T (2003) The lymphocytic cholinergic system and its contribution to the regulation of immune activity. Life Sci 74(6):675–696
Koennecke HC et al (2011) Factors influencing in-hospital mortality and morbidity in patients treated on a stroke unit. Neurology 77(10):965–972
Lahiri MK, Kannankeril PJ, Goldberger JJ (2008) Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications. J Am Coll Cardiol 51(18):1725–1733
Lau P, de Strooper B (2010) Dysregulated microRNAs in neurodegenerative disorders. Semin Cell Dev Biol 21(7):768–773
Lau P et al (2013) Alteration of the microRNA network during the progression of Alzheimer’s disease. EMBO Mol Med 5(10):1613–1634
Leeper NJ et al (2007) Prognostic value of heart rate increase at onset of exercise testing. Circulation 115(4):468–474
Lev-Lehman E et al (1997) Immature human megakaryocytes produce nuclear-associated acetylcholinesterase. Blood 89(10):3644–3653
Loewenstein-Lichtenstein Y et al (1995) Genetic predisposition to adverse consequences of anti-cholinesterases in ‘atypical’ BCHE carriers. Nat Med 1(10):1082–1085
Loewi O (1921) Über humorale Übertragbarkeit der Herznervenwirkung. I. Pflügers Archiv 189:239–242
Maharshak N et al (2013) MicroRNA-132 modulates cholinergic signaling and inflammation in human inflammatory bowel disease. Inflamm Bowel Dis 19(7):1346–1353
Massoulie J et al (2008) Old and new questions about cholinesterases. Chem Biol Interact 175(1–3):30–44
Mayer EA, Craske M, Naliboff BD (2001) Depression, anxiety, and the gastrointestinal system. J Clin Psychiatry 62(Suppl 8):28–36, discussion 37
McCafferty DM, Wallace JL, Sharkey KA (1997) Effects of chemical sympathectomy and sensory nerve ablation on experimental colitis in the rat. Am J Physiol 272(2 Pt 1):G272–G280
Meisel C, Meisel A (2011) Suppressing immunosuppression after stroke. N Engl J Med 365(22):2134–2136
Meregnani J et al (2011) Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci 160(1–2):82–89
Meshorer E et al (2002) Alternative splicing and neuritic mRNA translocation under long-term neuronal hypersensitivity. Science 295(5554):508–512
Meshorer E et al (2004) Combinatorial complexity of 5′ alternative acetylcholinesterase transcripts and protein products. J Biol Chem 279(28):29740–29751
Meshorer E et al (2006) Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell 10(1):105–116
Metz CN, Tracey KJ (2005) It takes nerve to dampen inflammation. Nat Immunol 6(8):756–757
Najarian RM et al (2006) Metabolic syndrome compared with type 2 diabetes mellitus as a risk factor for stroke: the Framingham Offspring Study. Arch Intern Med 166(1):106–111
Ofek K, Soreq H (2013) Cholinergic involvement and manipulation approaches in multiple system disorders. Chem Biol Interact 203(1):113–119
Ofek K et al (2007) Cholinergic status modulations in human volunteers under acute inflammation. J Mol Med (Berl) 85(11):1239–1251
Parnetti L, Chiasserini D (2011) Role of CSF biomarkers in the diagnosis of prodromal Alzheimer’s disease. Biomark Med 5(4):479–484
Perry EK et al (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 2(6150):1457–1459
Podoly E et al (2009) The butyrylcholinesterase K variant confers structurally derived risks for Alzheimer pathology. J Biol Chem 284(25):17170–17179
Pohjavaara P, Telaranta T, Vaisanen E (2003) The role of the sympathetic nervous system in anxiety: is it possible to relieve anxiety with endoscopic sympathetic block? Nord J Psychiatry 57(1):55–60
Prass K et al (2003) Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med 198(5):725–736
Pritchard CC, Cheng HH, Tewari M (2012) MicroRNA profiling: approaches and considerations. Nat Rev Genet 13(5):358–369
Rachakonda V, Pan TH, Le WD (2004) Biomarkers of neurodegenerative disorders: how good are they? Cell Res 14(5):347–358
Rao AA, Sridhar GR, Das UN (2007) Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer’s disease. Med Hypotheses 69(6):1272–1276
Rodriguez-Diaz R et al (2011) Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat Med 17:882–892
Roger VL et al (2012) Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125(1):e2–e220
Rosas-Ballina M et al (2011) Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334(6052):98–101
Sailaja BS et al (2012) Stress-induced epigenetic transcriptional memory of acetylcholinesterase by HDAC4. Proc Natl Acad Sci U S A 109(52):E3687–E3695
Savonen KP et al (2008) Chronotropic incompetence and mortality in middle-aged men with known or suspected coronary heart disease. Eur Heart J 29(15):1896–1902
Schwartz J (2000) Neurotransmitters. In: Kandel ER, Schwartz JH, Jessell TM (eds) Principles of neuronal science. McGraw-Hill, New-York, pp 281–297
Shaked I et al (2009) MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase. Immunity 31(6):965–973
Shaltiel G et al (2013) Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target. Brain Struct Funct 218(1):59–72
Shenhar-Tsarfaty S et al (2010) Interleukin-6 as an early predictor for one-year survival following an ischaemic stroke/transient ischaemic attack. Int J Stroke 5(1):16–20
Shenhar-Tsarfaty S et al (2011) Post-stroke cholinergic biomarkers. Science. Available at http://www.sciencemag.org/content/334/6052/101/reply
Shenhar-Tsarfaty S et al (2011b) Butyrylcholinesterase interactions with amylin may protect pancreatic cells in metabolic syndrome. J Cell Mol Med 15(8):1747–1756
Shishehbor MH, Hoogwerf BJ, Lauer MS (2004) Association of triglyceride-to-HDL cholesterol ratio with heart rate recovery. Diabetes Care 27(4):936–941
Sklan EH et al (2004) Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study. Proc Natl Acad Sci U S A 101(15):5512–5517
Soreq H, Seidman S (2001) Acetylcholinesterase—new roles for an old actor. Nat Rev Neurosci 2(4):294–302
Soreq H, Wolf Y (2011) NeurimmiRs: microRNAs in the neuroimmune interface. Trends Mol Med 17(10):548–555
Straznicky NE et al (2008) Mediators of sympathetic activation in metabolic syndrome obesity. Curr Hypertens Rep 10(6):440–447
Sykora M et al (2011) Autonomic shift and increased susceptibility to infections after acute intracerebral hemorrhage. Stroke 42(5):1218–1223
Thalamas C et al (2000) Glucose-induced sympathetic activity and energy expenditure during acute alpha2-adrenergic antagonism in obese subjects. Int J Obes Relat Metab Disord 24(6):695–700
Tracey KJ (2010) Understanding immunity requires more than immunology. Nat Immunol 11(7):561–564
Trakhtenberg EF, Goldberg JL (2011) Immunology neuroimmune communication. Science 334(6052):47–48
Wessler I, Kirkpatrick CJ (2008) Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol 154(8):1558–1571
Wessler I, Kirkpatrick CJ, Racke K (1998) Non-neuronal acetylcholine, a locally acting molecule, widely distributed in biological systems: expression and function in humans. Pharmacol Ther 77:59–79
Wong CH et al (2011) Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334(6052):101–105
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S.S-T is grateful to the Edmond and Lily Safra Center for Brain Science for post-doctoral fellowship.
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Shenhar-Tsarfaty, S., Berliner, S., Bornstein, N.M. et al. Cholinesterases as Biomarkers for Parasympathetic Dysfunction and Inflammation-Related Disease. J Mol Neurosci 53, 298–305 (2014). https://doi.org/10.1007/s12031-013-0176-4
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DOI: https://doi.org/10.1007/s12031-013-0176-4