Pathways of Acetylcholine Synthesis, Transport and Release as Targets for Treatment of Adult-Onset Cognitive Dysfunction

Abstract

Acetylcholine (ACh) is a neurotransmitter widely diffused in central, peripheral, autonomic and enteric nervous system. This paper has reviewed the main mechanisms of ACh synthesis, storage, and release. Presynaptic choline transport supports ACh production and release, and cholinergic terminals express a unique transporter critical for neurotransmitter release. Neurons cannot synthesize choline, which is ultimately derived from the diet and is delivered through the blood stream. ACh released from cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A and almost 50% of choline derived from ACh hydrolysis is recovered by a high-affinity choline transporter. Parallel with the development of cholinergic hypothesis of geriatric memory dysfunction, cholinergic precursor loading strategy was tried for treating cognitive impairment occurring in Alzheimer's disease. Controlled clinical studies denied clinical usefulness of choline and lecithin (phosphatidylcholine), whereas for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) or alpha-glyceryl-phosphorylcholine (choline alphoscerate) a modest improvement of cognitive dysfunction in adult-onset dementia disorders is documented. These inconsistencies have probably a metabolic explanation. Free choline administration increases brain choline availability but it does not increase ACh synthesis/or release. Cholinergic precursors to serve for ACh biosynthesis should be incorporate and stored into phospholipids in brain. It is probable that appropriate ACh precursors and other correlated molecules (natural or synthesized) could represent a tool for developing therapeutic strategies by revisiting and updating treatments/supplementations coming out from this therapeutic stalemate.

Effects of α-Glucosylhesperidin on the Peripheral Body Temperature and Autonomic Nervous System

“…38,39) The influence of acetylcholine on vasodilation is very much doubted, because acetylcholine released from parasympathetic cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A. 40) However, when the acetylcholine concentration is high, acetylcholinesterase is less effective in governing such thermoregulation as the sweat rate. 41) The indirect vasodilating effect might be related to the direct one, and both effects are considered to be cyclical processes under homeostatic conditions.…”

Quantification of acetylcholine, an essential neurotransmitter, in brain microdialysis samples by liquid chromatography mass spectrometry

“…ACh is biosynthesized in a reaction catalyzed by ChAT; it uses choline taken up SDHACU and mitochondrial bound ACo-A (Okuda et al, 2000). Acetylcholine is stored in vesicular form at the nerve terminals of cholinergic fi bers by the activity of a 12-transmembrane domain protein, the vesicular ACh transporter (VAChT) (Amenta and Tayebati, 2008). In response to an action potential, it is released by exocytosis into the synaptic cleft, from which it diff uses to the postsynaptic site for interaction with appropriate receptors (or postjunctional site outside the central nervous system), which results in specifi c eff ects according to the receptor type (nicotinic or muscarinic).…”

Citidine-5-diphosphocholine Ameliorates the Impairment of Spatial Memory Induced by Scopolamine

“…4,5) CDP-choline is a raw material for the synthesis of phospholipids, which are cell-membrane components required to maintain the structure of nerve cells. 6) However, the memory enhancing effect of CDP-choline may be due to increasing the supply of acetylcholine, because CDP-choline increases extracellular acetylcholine in the dorsal hippocampus and neocortex in normal rats.…”