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.