Intracellular redistribution of acetyl-CoA, the pivotal point in differential susceptibility of cholinergic neurons and glial cells to neurodegenerative signals

Abstract

Intramitochondrial decarboxylation of glucose-derived pyruvate by PDHC (pyruvate dehydrogenase complex) is a principal source of acetyl-CoA, for mitochondrial energy production and cytoplasmic synthetic pathways in all types of brain cells. The inhibition of PDHC, ACO (aconitase) and KDHC (ketoglutarate dehydrogenase complex) activities by neurodegenerative signals such as aluminium, zinc, amyloid β-peptide, excess nitric oxide (NO) or thiamine pyrophosphate deficits resulted in much deeper losses of viability, acetyl-CoA and ATP in differentiated cholinergic neuronal cells than in non-differentiated cholinergic, and cultured microglial or astroglial cell lines. In addition, in cholinergic cells, such conditions caused inhibition of ACh (acetylcholine) synthesis and its quantal release. Furthermore, cholinergic neuronal cells appeared to be resistant to high concentrations of LPS (lipopolysaccharide). In contrast, in microglial cells, low levels of LPS caused severalfold activation of NO, IL-6 (interleukin 6) and TNFα (tumour necrosis factor α) synthesis/release, accompanied by inhibition of PDHC, KDHC and ACO activities, and suppression of acetyl-CoA, but relatively small losses in their ATP contents and viability parameters. Compounds that protected these enzymes against inhibitory effects of neurotoxins alleviated acetyl-CoA and ATP deficits, thereby maintaining neuronal cell viability. These data indicate that preferential susceptibility of cholinergic neurons to neurodegenerative insults may result from competition for acetyl-CoA between mitochondrial energy-producing and cytoplasmic ACh-synthesizing pathways. Such a hypothesis is supported by the existence of highly significant correlations between mitochondrial/cytoplasmic acetyl-CoA levels and cell viability/transmitter functions respectively.

Increased Active OMI/HTRA2 Serine Protease Displays a Positive Correlation with Cholinergic Alterations in the Alzheimer’s Disease Brain

“…(1) As a matter of fact, biosynthesis of ACh is directly linked to mitochondrial glycolysis and citric acid cycle. In mitochondria, glucose converted to pyruvate, and thereby production of acetyl-Coenzyme A ( A-CoA ) [41], (2) which is partly used in the citric acid cycle for generation of bioenergetic molecules such as ATP, and (3) the rest may enter into the cytoplasm for instance for biosynthesis of ACh by ChAT, which is apparently required for activation of the mitochondrial nAChR ( mt- nAChR). (4) The mt-nAChRs and their regular activation by intracellular ACh may hence function as a biodynamic sensor.…”

Reactive Astrocytes in Neurodegenerative Diseases

“…The causes of these diseases are complex and still remain unknown, due to both genetic and sporadic issues. Neuropathological and radiological studies have shown that these diseases are accompanied by serious inflammation, during which the glial response may be a significant issue in the occurrence of neurons losses [42, 43]. Studies based on molecular biology show that the causes of neurodegenerative disorders are multi-systemic in vivo, and may be affected by a cascade of multiple signaling pathways [44].…”

The cAMP Inducers Modify N-Acetylaspartate Metabolism in Wistar Rat Brain

“…Mature neurons prefer mitochondrial energy metabolism instead of glycolysis [ 37 ]. This metabolic shift (tracked by pyruvate dehydrogenase (PDH) activity, acetyl-CoA and pyruvate levels) was clearly observed in primary neurons treated by either NGF or db-cAMP ( Table 3 , Figure 4 A,C).…”

“…To study cAMP—dependent protein kinase A activation using the in vivo model, we considered daily acute theophylline challenge instead of db-cAMP treatment. Theophylline injection has been proven to have a spread effect across the entire animal body (including the brain), while db-cAMP might not reach brain tissue, unless microinjected into the particular brain region [ 37 ].…”