Glucose-derived pyruvate is a principal source of acetyl-CoA in all brain cells, through pyruvate dehydogenase complex (PDHC) reaction. Cholinergic neurons like neurons of other transmitter systems and glial cells, utilize acetyl-CoA for energy production in mitochondria and diverse synthetic pathways in their extramitochondrial compartments. However, cholinergic neurons require additional amounts of acetyl-CoA for acetylcholine synthesis in their cytoplasmic compartment to maintain their transmitter functions. Characteristic feature of several neurodegenerating diseases including Alzheimer’s disease and thiamine diphosphate deficiency encephalopathy is the decrease of PDHC activity correlating with cholinergic deficits and losses of cognitive functions. Such conditions generate acetyl-CoA deficits that are deeper in cholinergic neurons than in noncholinergic neuronal and glial cells, due to its additional consumption in the transmitter synthesis. Therefore, any neuropathologic conditions are likely to be more harmful for the cholinergic neurons than for noncholinergic ones. For this reason attempts preserving proper supply of acetyl-CoA in the diseased brain, should attenuate high susceptibility of cholinergic neurons to diverse neurodegenerative conditions. This review describes how common neurodegenerative signals could induce deficts in cholinergic neurotransmission through suppression of acetyl-CoA metabolism in the cholinergic neurons.

Brain neurons, to support their neurotransmitter functions, require a several times higher supply of glucose than non-excitable cells. Pyruvate, the end product of glycolysis, through pyruvate dehydrogenase complex reaction, is a principal source of acetyl-CoA, which is a direct energy substrate in all brain cells. Several neurodegenerative conditions result in the inhibition of pyruvate dehydrogenase and decrease of acetyl-CoA synthesis in mitochondria. This attenuates metabolic flux through TCA in the mitochondria, yielding energy deficits and inhibition of diverse synthetic acetylation reactions in all neuronal sub-compartments. The acetyl-CoA concentrations in neuronal mitochondrial and cytoplasmic compartments are in the range of 10 and 7 μmol/L, respectively. They appear to be from 2 to 20 times lower than acetyl-CoA Km values for carnitine acetyltransferase, acetyl-CoA carboxylase, aspartate acetyltransferase, choline acetyltransferase, sphingosine kinase 1 acetyltransferase, acetyl-CoA hydrolase, and acetyl-CoA acetyltransferase, respectively. Therefore, alterations in acetyl-CoA levels alone may significantly change the rates of metabolic fluxes through multiple acetylation reactions in brain cells in different physiologic and pathologic conditions. Such substrate-dependent alterations in cytoplasmic, endoplasmic reticulum or nuclear acetylations may directly affect ACh synthesis, protein acetylations, and gene expression. Thereby, acetyl-CoA may regulate the functional and adaptative properties of neuronal and non-neuronal brain cells. The excitotoxicity-evoked intracellular zinc excess hits several intracellular targets, yielding the collapse of energy balance and impairment of the functional and structural integrity of postsynaptic cholinergic neurons. Acute disruption of brain energy homeostasis activates slow accumulation of amyloid-β_1-42 (Aβ). Extra and intracellular oligomeric deposits of Aβ affect diverse transporting and signaling pathways in neuronal cells. It may combine with multiple neurotoxic signals, aggravating their detrimental effects on neuronal cells. This review presents evidences that changes of intraneuronal levels and compartmentation of acetyl-CoA may contribute significantly to neurotoxic pathomechanisms of different neurodegenerative brain disorders.

The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections in each neuron. Astroglial, microglial and oligodendroglial cells and neurons reciprocally regulate the metabolism of key energy substrates, thereby exerting several neuroprotective, neurotoxic and regulatory effects on neuronal viability and neurotransmitter functions. Maintenance of the pool of mitochondrial acetyl-CoA derived from glycolytic glucose metabolism is a key factor for neuronal survival. Thus, acetyl-CoA is regarded as a direct energy precursor through the TCA cycle and respiratory chain, thereby affecting brain cell viability. It is also used for hundreds of acetylation reactions, including N-acetyl aspartate synthesis in neuronal mitochondria, acetylcholine synthesis in cholinergic neurons, as well as divergent acetylations of several proteins, peptides, histones and low-molecular-weight species in all cellular compartments. Therefore, acetyl-CoA should be considered as the central point of metabolism maintaining equilibrium between anabolic and catabolic pathways in the brain. This review presents data supporting this thesis.

Retinoic acid is a potent cell differentiating factor, which through its nuclear receptors affects a vast range of promoter sites in brain neuronal and glial cells in every step of embryonic and postnatal life. Its capacities, facilitating maturation of neurotransmitter phenotype in different groups of neurons, pave the way for its application as a potential therapeutic agent in neurodegenerative diseases including Alzheimer's disease. Retinoic acid was found to exert particularly strong enhancing effects on acetylcholine transmitter functions in brain cholinergic neurons, loss of which is tightly linked to the development of cognitive and memory deficits in course of different cholinergic encephalopathies. Here, we review cholinotrophic properties of retinoic acid and its derivatives, which may justify their application in the management of Alzheimer's disease and the related neurodegenerative conditions.