Phenotype-dependent susceptibility of cholinergic neuroblastoma cells to neurotoxic inputs

Abstract

A preferential loss of brain cholinergic neurons in the course of Alzheimer's disease and other encephalopathies is accompanied by a proportional impairment of acetyl-CoA synthesizing capacity in affected brains. Particular susceptibility of cholinergic neurons to neurodegeneration might results from insufficient supply of acetyl-CoA for energy production and acetylcholine synthesis in these conditions. Exposure of SN56 cholinergic neuroblastoma cells to dibutyryl cAMP and retinoic acid for 3 days caused their morphologic differentiation along with the increase in choline acetyltransferase activity, acetylcholine content and release, calcium content, and the expression of p75 neurotrophin receptors. Acetyl-CoA content correlated inversely with choline acetyltransferase activity in different lines of SN56 cells. In differentiated cells, aluminum (1 mM), amyloid beta(25-35) (0.001 mM), and sodium nitroprusside (1 mM), caused much greater decrease of pyruvate dehydrogenase and choline acetyltransferase activities and cell viability than in nondifferentiated ones. Aluminum (1 mM) aggravated suppressory effects of amyloid beta on choline acetyltransferase and pyruvate dehydrogenase activities and viability of differentiated cells. Similar additive inhibitory effects were observed upon combined exposure of differentiated cells to sodium nitroprusside and amyloid beta(25-35). None or much smaller suppressory effects of these neurotoxins were observed in nondifferentiated cells. Increase in the fraction of nonviable differentiated cells positively correlated with losses of choline acetyltransferase, pyruvate dehydrogenase activities, and cytoplasmic cytochrome c content in different neurotoxic conditions. These data indicate that highly differentiated cholinergic neurons may be more susceptible to aluminum and other neurotoxins than the nondifferentiated ones due to relative shortage of acetyl-CoA, increased content of Ca(2+), and expression of p75 receptors, yielding increase in cytoplasmic cytochrome c and subsequently grater rate of death of the former ones.

Degeneration of Cholinergic Rat Basal Forebrain Neurons After Experimental Subarachnoid Hemorrhage

“…Subsequently, the replenishment of the cellular ACh reservoir by its synthesis from acetyl-coenzyme A (CoA) and choline takes place. Because acetyl-CoA is not only used for ACh synthesis in these cells but also for energy and membrane phosphatidylserine synthesis (47), any shortage or insufficient supply of acetylCoA will result in either reduced transmitter activity by impaired ACh synthesis or in cellular degradation. Furthermore, cholinergic cells might use the choline bound in the cell membrane to produce ACh in cases of acetyl-CoA deficiency (53).…”

Early and Late Pathomechanisms in Alzheimer’s Disease: From Zinc to Amyloid-β Neurotoxicity

“…On the other hand, high activity of PDHC in neuronal cells would secure generally higher, transmitter type-independent energy demands of these brain cells irrespective of the synthesized transmitter. However, such feature of PDHC expression in neurons would make cholinergic ones more vulnerable than noncholinegric ones to neurodegeneration due to utilization of additional fraction of acetyl-CoA for ACh synthesis (next chapter) [6, 71]. …”

“…Cells transfection with additional copy of ChAT cDNA caused several fold elevations of ChAT activity and ACh content and over twofold decrease of whole cell acetyl-CoA. Thus, there is an inverse correlation between expression of cholinergic phenotype and size of acetyl-CoA pool in the cholinergic neurons [71, 75]. Highly cholinergic cells contain of less NAA, due to lower concentration of acetyl-CoA in their mitochondria decreasing velocity of aspartate-N-acetyltransferase reaction (EC 2.3.1.17.)…”

Does neurotransmission impairment accompany aluminium neurotoxicity?

“…It has been demonstrated that aluminium interferes with the metabolism of acetyl-CoA, leading to a decrease in mitochondrial acetyl-CoA content [110]. As elevated cholinergic activity stimulates acetyl-CoA synthesis in order to supply it for synthesis of acetylcholine, the deleterious effects of aluminium on this metabolic pathway are more prominent in cholinergic nerve terminals [111][112][113]. The choline used for the synthesis of acetylcholine is either transported from the synaptic cleft (see Section 6) to the presynaptic nerve terminal or is derived from phosphatidylcholine.…”