title: Regulated Extracellular Choline Acetyltransferase Activity- The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway.
abstract: Acetylcholine (ACh), the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT) in human cerebrospinal fluid (CSF) and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer's disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic signaling in states of inflammation in general and in neurodegenerative disease, such as Alzheimer's disease and multiple sclerosis in particular.
authors.affiliation: Division of Alzheimer Neurobiology Center, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Huddinge, Stockholm, Sweden.
authors.forename: Swetha
authors.initials: S
authors.lastname: Vijayaraghavan
authors.forename: Azadeh
authors.initials: A
authors.lastname: Karami
authors.forename: Shahin
authors.initials: S
authors.lastname: Aeinehband
authors.forename: Homira
authors.initials: H
authors.lastname: Behbahani
authors.forename: Alf
authors.initials: A
authors.lastname: Grandien
authors.forename: Bo
authors.initials: B
authors.lastname: Nilsson
authors.forename: Kristina N
authors.initials: KN
authors.lastname: Ekdahl
authors.forename: Rickard P F
authors.initials: RP
authors.lastname: Lindblom
authors.forename: Fredrik
authors.initials: F
authors.lastname: Piehl
authors.forename: Taher
authors.initials: T
authors.lastname: Darreh-Shori
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000097:blood / Q000134:cerebrospinal fluid; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000097:blood / Q000134:cerebrospinal fluid; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000201:enzymology; D051379:Mice; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000235:genetics
chemical_list: D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D000109:Acetylcholine