Inhibition of brain energy metabolism in demented subjects correlates with impairment their cognitive functions and loss of cholinergic neuron markers found in post mortem studies. However, mechanisms of preferential loss of brain cholinergic neurons in Alzheimer’s disease and other encephalopathies, remain unknown. We demonstrate that neuronal acetyl-CoA metabolism may be a primary target for neurodegenerative insults. Several putative encephalopathy-inducing pathogens, such as aluminum, amyloid-beta, zinc, NO excess, interleukin 1b, hypoglycemia and thiamine deficit were found to decrease viability and transmitter functions of cholinergic neuronal cells in cultures as well as in whole brain models of neurodegeneration. They caused inhibition of pyruvate dehydrogenase activity that correlated directly with respective alterations of acetyl-CoA level in neuronal mitochondria and inversely with rate of cell death. Moreover, these pathogens caused greater suppression mitochondrial acetyl-CoA and viability of differentiated than nondifferentiated cholinergic neuronal cells. Decreased availability of intramitochondrial acetyl-CoA apparently suppressed its transport to cytoplasm. In consequence, these neurotoxins decreased acetyl-CoA level in the cytoplasmic compartment. It resulted in a prominent decrease in ACh content and its quantal release in differentiated cells. In nondifferentiated cells neurotoxic effects were much smaller or negligible. Significant direct correlations were found between cytoplasmic acetyl-CoA levels and different parameters of cholinergic metabolism. Neurotoxic signals were less harmful for resting microglial and astroglial than for neuronal cells. Several compounds, known to improve pyruvate and acetyl-CoA metabolism, such as lipoamide, acetyl-L-carnitine, flavonoids, prevented neurotoxic activities through the maintenance proper level of acetyl-CoA in the mitochondrial compartment. They also, stabilized transmitter functions, when added simultaneously with neurotoxic compounds. However, delay in neuroprotectant application, abolished its beneficial effects on cell survival. It might be due to irreversible inhibition of aconitase and isocitrate dehydrogenase by some neurotoxins. Presented data indicate that in encephalopathic brains, cholinergic neurons viability and their transmitter functions are affected by alterations of two functionally independent pools of intramitochondrial and cytoplasmic acetyl-CoA, respectively. Supported by MNiSW projects NN401233333, 401029937 and GUMed fund St-57.
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