Effects of Marginal Zn Excess and Thiamine Deficiency on Microglial N9 Cell Metabolism and Their Interactions with Septal SN56 Cholinergic Cells.

Mild thiamine deficiency aggravates Zn accumulation in cholinergic neurons. It leads to the augmentation of Zn toxicity by its interaction with the enzymes of energy metabolism. Within this study, we tested the effect of Zn on microglial cells cultivated in a thiamine-deficient medium, containing 0.

Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism.

Background: Astrocytes play a central role in maintaining brain energy metabolism, but are also tightly connected to the pathogenesis of Alzheimer's disease (AD). Our previous studies demonstrate that inflammatory astrocytes accumulate large amounts of aggregated amyloid-beta (Aβ). However, in which way these Aβ deposits influence their energy production remain unclear.

Resveratrol Inhibits Metabolism and Affects Blood Platelet Function in Type 2 Diabetes.

Chronic hyperglycemia contributes to vascular complications in diabetes. Resveratrol exerts anti-diabetic and anti-platelet action. This study aimed to evaluate the effects of resveratrol on metabolism and the function of blood platelets under static and in in vitro flow conditions in patients with type 2 diabetes.

Protection of Cholinergic Neurons against Zinc Toxicity by Glial Cells in Thiamine-Deficient Media.

Brain pathologies evoked by thiamine deficiency can be aggravated by mild zinc excess. Cholinergic neurons are the most susceptible to such cytotoxic signals. Sub-toxic zinc excess aggravates the injury of neuronal SN56 cholinergic cells under mild thiamine deficiency.

Traumatic brain injury in the presence of Aβ pathology affects neuronal survival, glial activation and autophagy.

Traumatic brain injury (TBI) presents a widespread health problem in the elderly population. In addition to the acute injury, epidemiological studies have observed an increased probability and earlier onset of dementias in the elderly following TBI. However, the underlying mechanisms of the connection between TBI and Alzheimer's disease in the aged brain and potential exacerbating factors is still evolving.

Role of Energy Metabolism in the Progression of Neuroblastoma.

Neuroblastoma is a common childhood cancer possessing a significant risk of death. This solid tumor manifests variable clinical behaviors ranging from spontaneous regression to widespread metastatic disease. The lack of promising treatments calls for new research approaches which can enhance the understanding of the molecular background of neuroblastoma.

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

Neuronal -acetylaspartate production appears in the presence of aspartate -acetyltransferase (NAT8L) and binds acetyl groups from acetyl-CoA with aspartic acid. Further -acetylaspartate pathways are still being elucidated, although they seem to involve neuron-glia crosstalk. Together with -acetylaspartate, NAT8L takes part in oligoglia and astroglia cell maturation, myelin production, and dopamine-dependent brain signaling.

Neither Excessive Nitric Oxide Accumulation nor Acute Hyperglycemia Affects the -Acetylaspartate Network in Wistar Rat Brain Cells.

The -acetylaspartate network begins in neurons with -acetylaspartate production catalyzed by aspartate -acetyltransferase from acetyl-CoA and aspartate. Clinical studies reported a significant depletion in -acetylaspartate brain level in type 1 diabetic patients. The main goal of this study was to establish the impact of either hyperglycemia or oxidative stress on the -acetylaspartate network.

The Impact of Acetyl-CoA and Aspartate Shortages on the N-Acetylaspartate Level in Different Models of Cholinergic Neurons.

N-acetylaspartate is produced by neuronal aspartate N-acetyltransferase (NAT8L) from acetyl-CoA and aspartate. In cholinergic neurons, acetyl-CoA is also utilized in the mitochondrial tricarboxylic acid cycle and in acetylcholine production pathways. While aspartate has to be shared with the malate-aspartate shuttle, another mitochondrial machinery together with the tricarboxylic acid cycle supports the electron transport chain turnover.

Inhibition of pyruvate dehydrogenase complex activity by 3-bromopyruvate affects blood platelets responses in type 2 diabetes.

Background: Hyperactivation of blood platelets is an essential factor in the pathomechanism of diabetes-evoked angiopathies. The aim of this work was to investigate whether blood platelets hyperactivation resulting from type 2 diabetic hyperglycaemia-increased pyruvate dehydrogenase complex activity and excessive acetyl-CoA accumulation may be brought to the normal range by the enzyme inhibitors.

Methods: Platelets were isolated from the blood of 9 type 2 diabetic patients and 10 healthy donors.

Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting over 10% of the elderly population. Epidemiological evidence indicates that traumatic brain injury (TBI) is an important risk factor for developing AD later in life. However, which injury-induced processes that contribute to the disease onset remains unclear.

Aggravated effects of coexisting marginal thiamine deficits and zinc excess on SN56 neuronal cells.

Zinc excitotoxicity and thiamine pyrophosphate deficiency (TD) are known pathogenic signals contributing to mechanism of different encephalopathies through inhibition of enzymes responsible for energy metabolism such as pyruvate dehydrogenase, aconitase or ketoglutarate dehydrogenase. The aim of this work was to investigate whether subclinical Zn excess and TD, frequent in aging brain, may combine yielding overt neuronal impairment. Clonal SN56 cholinergic neuronal cells of septal origin were used as the model of brain cholinergic neurons, which are particularly susceptible to neurodegeneration in the course of Alzheimer's disease, hypoxia and other dementia-linked brain pathologies.

Protective effects of voltage-gated calcium channel antagonists against zinc toxicity in SN56 neuroblastoma cholinergic cells.

One of the pathological site effects in excitotoxic activation is Zn2+ overload to postsynaptic neurons. Such an effect is considered to be equivalent to the glutamate component of excitotoxicity. Excessive uptake of Zn2+ by active voltage-dependent transport systems in these neurons may lead to significant neurotoxicity.

The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain.

Brain neurons, to support their neurotransmitter functions, require a several times higher supply of glucose than non-excitable cells. Pyruvate, the end product of glycolysis, through pyruvate dehydrogenase complex reaction, is a principal source of acetyl-CoA, which is a direct energy substrate in all brain cells. Several neurodegenerative conditions result in the inhibition of pyruvate dehydrogenase and decrease of acetyl-CoA synthesis in mitochondria.

The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death.

Background: Currently, several amyloid beta (Aβ) antibodies, including the protofibril selective antibody BAN2401, are in clinical trials. The murine version of BAN2401, mAb158, has previously been shown to lower the levels of pathogenic Aβ and prevent Aβ deposition in animal models of Alzheimer's disease (AD). However, the cellular mechanisms of the antibody's action remain unknown.

Phenotype-Dependent Interactions between N-acetyl-L-Aspartate and Acetyl-CoA in Septal SN56 Cholinergic Cells Exposed to an Excess of Zinc.

Pyruvate dehydrogenase reaction utilizing glucose-derived pyruvate is an almost exclusive source of acetyl-CoA in different cell mitochondrial compartments of the brain. In neuronal mitochondria, the largest fraction of acetyl-CoA is utilized for energy production and the much smaller one for N-acetyl-L-aspartate (NAA) synthesis. Cholinergic neurons, unlike others, require additional amounts of acetyl-CoA for acetylcholine synthesis.

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

There are several systemic and intracerebral pathologic conditions, which limit provision and utilization of energy precursor metabolites in neuronal cells. Energy deficits cause excessive depolarization of neuronal cells triggering glutamate-zinc evoked excitotoxic cascade. The intracellular zinc excess hits several intraneuronal targets yielding collapse of energy balance and impairment functional and structural impairments cholinergic neurons.

Differential effects of lipopolysaccharide on energy metabolism in murine microglial N9 and cholinergic SN56 neuronal cells.

There are significant differences between acetyl-CoA and ATP levels, enzymes of acetyl-CoA metabolism, and toll-like receptor 4 contents in non-activated microglial N9 and non-differentiated cholinergic SN56 neuroblastoma cells. Exposition of N9 cells to lipopolysaccharide caused concentration-dependent several-fold increases of nitrogen oxide synthesis, accompanied by inhibition of pyruvate dehydrogenase complex, aconitase, and α-ketoglutarate dehydrogenase complex activities, and by nearly proportional depletion of acetyl-CoA, but by relatively smaller losses in ATP content and cell viability (about 5%). On the contrary, SN56 cells appeared to be insensitive to direct exposition to high concentration of lipopolysaccharide.

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

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.

Effects of sodium metavanadate on in vitro neuroblastoma and red blood cells.

Toxicity of vanadium on cells is one of the less studied effects. This prompted us to study the structural effects induced on neuroblastoma and erythrocytes by vanadium (V) sodium metavanadate. This salt was incubated with mice cholinergic neuroblastoma cells and intact human erythrocytes.