Preferential loss of brain cholinergic neurons in course of Alzheimerís disease (AD) and other encephalopathies might result from the fact that they utilize acetyl-CoA, not only for energy and N-acetylaspartate production but also for acetylcholine (ACh) synthesis. Therefore, acetyl-CoA metabolism might be a likely target for both cytotoxic signals and therapeutic procedures. The shortage of acetyl-CoA in cholinergic cell mitochondria caused their high susceptibility to amyloid-beta, NO, Al and Zn. They caused dose-dependent increase of nonviable cell fraction and cytoplasmic cytochrome c levels, decreases in mitochondrial enzyme and ChAT activities, intramitochondrial and cytoplasmic acetyl-CoA and ACh levels, with loss of morphologic differentiation. The expression of cholinergic phenotype positively correlated with compound-evoked alterations in cytoplasmic acetylCoA levels (r=0.90, P=0.002). On the other hand, cytoprotective properties correlated with their ability to maintain high level of acetyl-CoA in mitochondria. Accordingly nonviable cell fraction inversely correlated with pyruvate dehydrogenase activity (r=−0.79, P=0.002) and content of mitochondrial acetyl-CoA (r=−0.92, P=0.0002). These data indicate the existence in cholinergic neurons two independent pools of cytoplasmic and mitochondrial acetyl-CoA, that under pathologic conditions affect expression of cholinergic phenotype and their viability, respectively. Supported by MNiSW project 2P05A 110 30
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