The neurotoxicity of phosphorylated tau protein (P-tau) and mitochondrial dysfunction play a significant role in the pathophysiology of Alzheimer's disease (AD). In vitro studies of the effects of P-tau oligomers on mitochondrial bioenergetics and reactive oxygen species production will allow us to evaluate the direct influence of P-tau on mitochondrial function. We measured the in vitro effect of P-tau oligomers on oxygen consumption and hydrogen peroxide production in isolated brain mitochondria. An appropriate combination of specific substrates and inhibitors of the phosphorylation pathway enabled the measurement and functional analysis of the effect of P-tau on mitochondrial respiration in defined coupling control states achieved in complex I-, II-, and I&II-linked electron transfer pathways. At submicromolar P-tau concentrations, we found no significant effect of P-tau on either mitochondrial respiration or hydrogen peroxide production in different respiratory states. The titration of P-tau showed a nonsignificant dose-dependent decrease in hydrogen peroxide production for complex I- and I&II-linked pathways. An insignificant in vitro effect of P-tau oligomers on both mitochondrial respiration and hydrogen peroxide production indicates that P-tau-induced mitochondrial dysfunction in AD is not due to direct effects of P-tau on the efficiency of the electron transport chain and on the production of reactive oxygen species.

• Keywords
• Alzheimer’s disease, hydrogen peroxide, isolated mitochondria, mitochondrial dysfunction, phosphorylated tau, respiratory state,
• MeSH
• Cell Respiration MeSH
• Phosphorylation MeSH
• Rats MeSH
• Humans MeSH
• Mitochondria * metabolism   MeSH
• Brain metabolism   MeSH
• Hydrogen Peroxide * metabolism   MeSH
• tau Proteins * metabolism   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Oxygen Consumption MeSH
• Electron Transport MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hydrogen Peroxide * MeSH
• tau Proteins * MeSH
• Reactive Oxygen Species MeSH

Mitochondrial dysfunction is involved in the pathophysiology of psychiatric and neurodegenerative disorders and can be used as a modulator and/or predictor of treatment responsiveness. Understanding the mitochondrial effects of antidepressants is important to connect mitochondria with their therapeutic and/or adverse effects. Pig brain-isolated mitochondria were used to evaluate antidepressant-induced changes in the activity of electron transport chain (ETC) complexes, monoamine oxidase (MAO), mitochondrial respiratory rate, and ATP. Bupropion, escitalopram, fluvoxamine, sertraline, paroxetine, and trazodone were tested. All tested antidepressants showed significant inhibition of complex I and IV activities at high concentrations (50 and 100 µmol/L); complex II + III activity was reduced by all antidepressants except bupropion. Complex I-linked respiration was reduced by escitalopram >> trazodone >> sertraline. Complex II-linked respiration was reduced only by bupropion. Significant positive correlations were confirmed between complex I-linked respiration and the activities of individual ETC complexes. MAO activity was inhibited by all tested antidepressants, with SSRIs causing a greater effect than trazodone and bupropion. The results indicate a probable association between the adverse effects of high doses of antidepressants and drug-induced changes in the activity of ETC complexes and the respiratory rate of mitochondria. In contrast, MAO inhibition could be linked to the antidepressant, procognitive, and neuroprotective effects of the tested antidepressants.

• Keywords
• ATP, antidepressants, mitochondrial respiration, monoamine oxidase, oxidative phosphorylation, reactive oxygen species,
• Publication type
• Journal Article MeSH

Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

• Keywords
• Alzheimer’s disease, amyloid beta, drug, mitochondria, tau protein,
• MeSH
• Alzheimer Disease * metabolism   MeSH
• Amyloid metabolism   MeSH
• Amyloid beta-Peptides metabolism   MeSH
• Amyloidogenic Proteins metabolism   MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Amyloid MeSH
• Amyloid beta-Peptides MeSH
• Amyloidogenic Proteins MeSH

This article describes acetylcholinesterase (AChE), an enzyme involved in parasympathetic neurotransmission, its activity, and how its inhibition can be pharmacologically useful for treating dementia, caused by Alzheimer's disease, or as a warfare method due to the action of nerve agents. The chemical concepts related to the irreversible inhibition of AChE, its reactivation, and aging are discussed, along with a relationship to the current international legislation on chemical weapons.

• Keywords
• Alzheimer’s disease, Chemical Weapons Convention, acetylcholinesterase, nerve agents,
• MeSH
• Acetylcholinesterase * metabolism   MeSH
• Alzheimer Disease * drug therapy   enzymology   MeSH
• Chemical Warfare legislation & jurisprudence   MeSH
• Cholinesterase Inhibitors therapeutic use   MeSH
• GPI-Linked Proteins antagonists & inhibitors   metabolism   MeSH
• Humans MeSH
• Nerve Agents * MeSH
• Aging metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Acetylcholinesterase * MeSH
• ACHE protein, human MeSH Browser
• Cholinesterase Inhibitors MeSH
• GPI-Linked Proteins MeSH
• Nerve Agents * MeSH

Impairment of mitochondrial metabolism, particularly the electron transport chain (ETC), as well as increased oxidative stress might play a significant role in pathogenesis of Alzheimer's disease (AD). Some effects of drugs used for symptomatic AD treatment may be related to their direct action on mitochondrial function. In vitro effects of pharmacologically different cognitives (galantamine, donepezil, rivastigmine, 7-MEOTA, memantine) and nootropic drugs (latrepirdine, piracetam) were investigated on selected mitochondrial parameters: activities of ETC complexes I, II + III, and IV, citrate synthase, monoamine oxidase (MAO), oxygen consumption rate, and hydrogen peroxide production of pig brain mitochondria. Complex I activity was decreased by galantamine, donepezil, and memantine; complex II + III activity was increased by galantamine. None of the tested drugs caused significant changes in the rate of mitochondrial oxygen consumption, even at high concentrations. Except galantamine, all tested drugs were selective MAO-A inhibitors. Latrepirdine, donepezil, and 7-MEOTA were found to be the most potent MAO-A inhibitors. Succinate-induced mitochondrial hydrogen peroxide production was not significantly affected by the drugs tested. The direct effect of cognitives and nootropics used in the treatment of AD on mitochondrial respiration is relatively small. The safest drugs in terms of disturbing mitochondrial function appear to be piracetam and rivastigmine. The MAO-A inhibition by cognitives and nootropics may also participate in mitochondrial neuroprotection. The results support the future research aimed at measuring the effects of currently used drugs or newly synthesized drugs on mitochondrial functioning in order to understand their mechanism of action.

• Keywords
• Cognitives, Mitochondrial respiration, Monoamine oxidase, Nootropics, Reactive oxygen species,
• MeSH
• Alzheimer Disease metabolism   MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Donepezil MeSH
• Galantamine metabolism   MeSH
• Indans pharmacology   MeSH
• Cognition drug effects   MeSH
• Memantine pharmacology   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Monoamine Oxidase drug effects   metabolism   MeSH
• Brain drug effects   metabolism   MeSH
• Nootropic Agents pharmacology   MeSH
• Piperidines pharmacology   MeSH
• Swine MeSH
• Rivastigmine pharmacology   MeSH
• Oxygen Consumption drug effects   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholinesterase Inhibitors MeSH
• Donepezil MeSH
• Galantamine MeSH
• Indans MeSH
• Memantine MeSH
• Monoamine Oxidase MeSH
• Nootropic Agents MeSH
• Piperidines MeSH
• Rivastigmine MeSH