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.

Highlights

  • Inflammatory processes are involved in the pathogenesis of a variety of degenerative diseases, such as Alzheimer’s disease (AD), multiple sclerosis (MS) and rheumatoid arthritis (RA)

  • To the best of our knowledge, these analyses show for the first time that ChAT, like its counteracting enzymes AChE and BuChE, might exist as a variety of multimeric molecular forms in cerebrospinal fluids (CSF) and plasma

  • We demonstrated a number of findings that constitute compelling evidence that the acetylcholine-synthesizing enzyme, ChAT, is an intracellular enzyme present in the cytosol of cholinergic cells, but is present in extracellular compartments

Read more

Summary

Introduction

Inflammatory processes are involved in the pathogenesis of a variety of degenerative diseases, such as Alzheimer’s disease (AD), multiple sclerosis (MS) and rheumatoid arthritis (RA). More recent studies have established that acetylcholine (ACh), the classical neurotransmitter in the central and peripheral nervous systems, acts as a suppressor of inflammatory responses of lymphocytes, mediated by binding to a7-nicotinic ACh receptors (a7-nAChRs) [1]. This is known as the cholinergic anti-inflammatory pathway, by which the nervous system is proposed to exert immunomodulatory effects on systemic immunity [2,3]. The immune-suppressive activity requires that ACh has to be present at certain extrasynaptic levels to exert its putative role on immune cells by way of activating a7-nAChR ion-channels

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call