Interaction of Oxidative Stress and Misfolded Proteins in the Mechanism of Neurodegeneration

Abramov, Andrey Y.; Potapova, Elena; Dremin, Viktor; Dunaev, Andrey V.

doi:10.3390/life10070101

Cited by 64 publications

(63 citation statements)

References 109 publications

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“…In the current study, we found that oxidative stress specifically caused by the Aβ 1-42 -induced activation of NAD(P)H oxidase (NOX) underlies glucose metabolism deficiency. It was previously reported in multiple cell types that Aβ 1-42 induces brain oxidative stress (21), largely via activation of NOX (22)(23)(24). We show in vivo that NOX activation by oligomeric Aβ 1-42 results in pathological changes in brain glucose consumption, hippocampal network hyperactivity, and neuropsychiatric-like disturbances in the behavior of mice-all abnormalities that can be prevented by administration of the novel selective NOX2 antagonist GSK2795039.…”

Section: Introductionmentioning

confidence: 53%

“…In that context, the likely source of the H 2 O 2 and actual trigger of seizures is the reactive oxygen species (ROS)-generating NAD(P)H oxidase (NOX) (32). Aβ 1-42 has been reported to induce oxidative stress in multiple cell types by activating NOX (21)(22)(23)(24). Therefore, we asked whether the toxic effect of Aβ on glucose metabolism was mediated by NOX activation.…”

Section: Aβ 1-42 Toxicity Is Prevented By Blockade Of Nox2mentioning

confidence: 99%

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Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease

Malkov

Popova

Ivanov

et al. 2020

Preprint

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A paramount driver of sporadic Alzheimer's disease (AD) is the synergy of oxidative stress and glucose hypometabolism in the brain. Oxidative stress damages cellular macromolecules such as DNA, lipids and proteins, whereas glucose hypometabolism impairs cellular energy supply and antioxidant defence; Together, these cellular and functional alterations may be primary triggers of AD. However, the exact molecular basis of AD-associated glucose hypometabolism has remained unknown, hampering the search for effective interventions. Here, we identify NADPH oxidase 2 (NOX2) activation by beta-amyloid peptide (Aβ1-42) as the main molecular source of oxidative stress driving brain glucose hypometabolism and network hyperactivity. Using a combination of electrophysiology with dynamic recordings of autofluorescence and metabolic biosensors, we show that in hippocampal brain slices, Aβ1-42 application reduced network activity-driven glucose consumption and glycolysis by half, while NOX2 antagonism prevented this effect. In vivo, intracerebroventricular injection of Aβ1-42 exerted a profound inhibitory effect on brain glucose consumption, resulting in long-lasting network hyperactivity and changes in animal behavioral profile. Critically, the novel bioavailable NOX2 antagonist GSK2795039 prevented all of the observed Aβ-related detrimental effects. These data suggest that targeting NOX2-induced oxidative stress is a promising approach to both the prevention and treatment of AD.

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Section: Introductionmentioning

confidence: 53%

Section: Aβ 1-42 Toxicity Is Prevented By Blockade Of Nox2mentioning

confidence: 99%

Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease

Malkov

Popova

Ivanov

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Neurodegenerative diseases, as diverse group ailments, are characterized by progressive loss of neuronal cells in the targeted brain regions [33]. The pathophysiology of neurodegeneration is not yet fully understood; however, elevated oxidative stress has been indicated as one of the major factors responsible for the degeneration of neuronal cells [34,35]. Elevated oxidative stress may induce cellular damage, impair the DNA repair system, and trigger mitochondrial apoptosis, all of which are likened with aging and neurodegeneration [36,37].…”

Section: Pathological Bases Of Oxidative Stress and Neuroinflammationmentioning

confidence: 99%

Antioxidant and Neuroprotective Effects of Caffeine against Alzheimer’s and Parkinson’s Disease: Insight into the Role of Nrf-2 and A2AR Signaling

et al. 2020

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This paper reviews the results of studies conducted on the role of caffeine in the management of different neurological disorders, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). To highlight the potential role of caffeine in managing different neurodegenerative diseases, we identified studies by searching PubMed, Web of Science, and Google Scholar by scrutinizing the lists of pertinent publications. According to the collected overall findings, caffeine may reduce the elevated oxidative stress; inhibit the activation of adenosine A2A, thereby regulating the accumulation of Aβ; reduce the hyperphosphorylation of tau; and reduce the accumulation of misfolded proteins, such as α-synuclein, in Alzheimer’s and Parkinson’s diseases. The studies have suggested that caffeine has promising protective effects against different neurodegenerative diseases and that these effects may be used to tackle the neurological diseases and/or their consequences. Here, we review the ongoing research on the role of caffeine in the management of different neurodegenerative disorders, focusing on AD and PD. The current findings suggest that caffeine produces potent antioxidant, inflammatory, and anti-apoptotic effects against different models of neurodegenerative disease, including AD, PD, and other neurodegenerative disorders. Caffeine has shown strong antagonistic effects against the adenosine A2A receptor, which is a microglial receptor, and strong agonistic effects against nuclear-related factor-2 (Nrf-2), thereby regulating the cellular homeostasis at the brain by reducing oxidative stress, neuroinflammation, regulating the accumulation of α-synuclein in PD and tau hyperphosphorylation, amyloidogenesis, and synaptic deficits in AD, which are the cardinal features of these neurodegenerative diseases.

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“…For instance, a slow conversion of early, easy-degradable aggregates into compact, highly structured oligomers was detected in α-synuclein fibrillization [13], which is related to the progress of Parkinson's disease. These later oligomers induce much higher levels of reactive oxygen species (ROS) in cells than do earlier oligomers [14]. While focusing on Aβ aggregation, these oligomers interact with lipid membrane surfaces through weak electrostatic interactions that promote conformational transition from α-helix structures to β-sheet conformations [15].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, it has been observed that Aβ alters membrane phospholipid fluidity through its own insertion into lipid bilayers [16]. That insertion, in form of pores, induces calcium-signaling, activating NADPH oxidase, stimulating nitric oxide production, and finally leading to increased oxidative stress and to neurodegeneration [14,[17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Seeding and Growth of β-Amyloid Aggregates upon Interaction with Neuronal Cell Membranes

Ruiz-Arias

Paredes

Biase

et al. 2020

IJMS

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In recent years, the prevalence of amyloid neurodegenerative diseases such as Alzheimer’s disease (AD) has significantly increased in developed countries due to increased life expectancy. This amyloid disease is characterized by the presence of accumulations and deposits of β-amyloid peptide (Aβ) in neuronal tissue, leading to the formation of oligomers, fibers, and plaques. First, oligomeric intermediates that arise during the aggregation process are currently thought to be primarily responsible for cytotoxicity in cells. This work aims to provide further insights into the mechanisms of cytotoxicity by studying the interaction of Aβ aggregates with Neuro-2a (N2a) neuronal cells and the effects caused by this interaction. For this purpose, we have exploited the advantages of advanced, multidimensional fluorescence microscopy techniques to determine whether different types of Aβ are involved in higher rates of cellular toxicity, and we measured the cellular stress caused by such aggregates by using a fluorogenic intracellular biothiol sensor. Stress provoked by the peptide is evident by N2a cells generating high levels of biothiols as a defense mechanism. In our study, we demonstrate that Aβ aggregates act as seeds for aggregate growth upon interacting with the cellular membrane, which results in cell permeability and damage and induces lysis. In parallel, these damaged cells undergo a significant increase in intracellular biothiol levels.

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Interaction of Oxidative Stress and Misfolded Proteins in the Mechanism of Neurodegeneration

Cited by 64 publications

References 109 publications

Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease

Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease

Antioxidant and Neuroprotective Effects of Caffeine against Alzheimer’s and Parkinson’s Disease: Insight into the Role of Nrf-2 and A2AR Signaling

Seeding and Growth of β-Amyloid Aggregates upon Interaction with Neuronal Cell Membranes

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