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Cholinergic neurons, unlike other brain cells utilize acetyl-CoA not only for energy production but also for acetylcholine (ACh) synthesis. Therefore,, suppression of acetyl-CoA metabolism by different neurotoxic inputs may be particularly harmful for this group of cells. Differentiation of SN56 cholinergic hybrid cells increased their choline acetyltransferase (ChAT) activity and ACh content but depressed pyruvate dehydrogenase activity and acetyl-CoA content. Differentiated cells were more susceptible to acute and chronic influences of aluminum, NO and amyloid-β. Al decreased acetyyl-CoA content, ACh release and increased Ca accumulation in differentiated cells (DC) to much higher degree than in non-differentiated ones (NC). NO strongly depressed acetyl-CoA level and increased ACh release in DC but did not affect NC. Additive effects of Al and NO were seen in DC but not in NC. Also long term suppressory effects of amyloid-β, Al and NO on cholinergic phenotype and morphologic maturation were more evident in DC than in NC. Thus, relative shortage of acetyl-CoA in highly differentiated cholinergic neurons could make them particulary susceptible to degenerative insults in the course of different cholinergic encephalopathies. [ABSTRACT FROM AUTHOR]

Cholinergic neurons, unlike other brain cells utilize acetyl-CoA not only for energy production but also for acetylcholine (ACh) synthesis. Therefore, suppression of acetyl-CoA metabolism by different neurotoxic inputs may be particularly harmful for this group of cells. Differentiation of SN56 cholinergic hybrid cells increased their choline acetyltransferase (ChAT) activity and ACh content but depressed pyruvate dehydrogenase activity and acetyl-CoA content. Differentiated cells were more susceptible to acute and chronic influences of aluminum, NO and amyloid-β. Al decreased acetyl-CoA content, ACh release and increased Ca accumulation in differentiated cells (DC) to much higher degree than in non-differentiated ones (NC). NO strongly depressed acetyl-CoA level and increased ACh release in DC but did not affect NC. Additive effects of Al and NO were seen in DC but not in NC. Also long term suppressory effects of amyloid-β, Al and NO on cholinergic phenotype and morphologic maturation were more evident in DC than in NC. Thus, relative shortage of acetyl-CoA in highly differentiated cholinergic neurons could make them particularly susceptible to degenerative insults in the course of different cholinergic encephalopathies. [ABSTRACT FROM AUTHOR]

In potassium-depolarized synaptosomes Ca inhibited oxidation of pyruvate (30%) and decreased the level of acetyl-CoA in intrasynaptosomal mitochondria (32%). On the other hand, Ca facilitated provision of acetyl-CoA to synaptoplasm, since under these condition no change of synaptoplasmic acetyl-CoA and twofold stimulation of acetylcholine synthesis were found. However, in Ca-activated synaptosomes both synaptoplasmic acetyl-CoA and acetylcholine synthesis were suppressed by 1 mM (−)hydroxycitrate by 27 and 29%, respectively. It was not the case in resting synaptosomes. Dichloroacetate (0.05 mM) partially reversed the inhibitory effect of Ca on pyruvate metabolism in synaptosomes and whole brain mitochondria. In Ca-stimulated synaptosomes, the dichloroacetate overcame suppressive effects of (−)hydroxycitrate on the level of synaptoplasmic acetyl-CoA and acetylcholine synthesis, but not on citrate clevage. It is concluded that dichloroacetate may improve the metabolism of acetylcholine in activated cholinergic terminals by increasing the production of acetyl-CoA in mitochondria and increasing its provision through the mitochondrial membrane to synaptoplasm by the transport system, independent of the ATP-citrate lyase pathway. [ABSTRACT FROM AUTHOR]

The activity of ATP-citrate lyase in homogenates of five selected rat brain regions varied from 2.93 to 6.90 nmol/min/mg of protein in the following order: cerebellum < hippocampus < parietal cortex < striatum < medulla oblongata and that of the choline acetyltransferase from 0.15 to 2.08 nmol/min/mg of protein in cerebellum < parietal cortex < hippocampus=medulla oblongata < striatum. No substantial differences were found in regional activities of lactate dehydrogenase, pyruvate dehydrogenase, citrate synthase or acetyl-CoA synthase. High values of relative specific activities for both choline acetyltransferase and ATP-citrate lyase were found in synaptosomal and synaptoplasmic fractions from regions with a high content of cholinergic nerve endings. There are significant correlations between these two enzyme activities in general cytocol (S), synaptosomal (B) and synaptoplasmic (B) fractions from the different regions ( r=0.92-0.99). These data indicate that activity of ATP-citrate lyase in cholinergic neurons is several times higher than that present in glial and noncholinergic neuronal cells. [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF) is important for differentiation and maintenance of septal cholinergic neurons. It caused concentration-dependent increase of choline acetyltransferase (ChAT) activity ([EC50%] 1 ng/mL), acetylcholine (ACh) content and morphologic maturation of SN56TrkA(+)p75(+) but not TrkA(–)p75(+) cells. NGF added with cyclic AMP altered significantly differential effects of the latter neither in TrkA(–) nor TrkA(+). However, when cyclic AMP-predifferentiated cells were treated with NGF alone, it caused suppression of the cholinergic phenotype in both cell lines. Anti-p75 antibodies totally reversed inhibitory effects of NGF on ChAT activity. Differentiation was accompanied by increase whereas its reversal by decrease of intracellular Ca content. These data indicate that NGF may exert opposite effects on phenotype of cholinergic neurons by p75 receptor signaling pathways and changes in intracellular Ca. Acknowledgement: Supported by KBN project 6P05A 01020. [ABSTRACT FROM AUTHOR]