Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Neurodegenerative Diseases: Mechanisms and Therapy

Hou, Liyan; Zhang, Lin; Hong, Jau‐Shyong; Zhang, Dan; Zhao, Jie; Wang, Qingshan

doi:10.1089/ars.2019.8014

Cited by 30 publications

(27 citation statements)

References 191 publications

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“…The enzyme consists of a membrane-bound catalytic core and several cytosolic regulatory subunits (Bedard and Krause, 2007). There are seven known isoforms of NOX with NOX1, NOX2 and NOX4 expressed in multiple brain regions including the cerebral cortex, hippocampus, cerebellum, hypothalamus, midbrain and/or striatum (Hou et al, 2020). These NOX variants are the most prominent isoforms detected in a variety of brain cell types (Cahill-Smith and Li, 2014;Hou et al, 2020;Rastogi et al, 2016), with NOX2 the dominant form expressed by microglia, neurons, and astrocytes.…”

Section: The Cytoplasmic Antioxidant Systemmentioning

confidence: 99%

“…There are seven known isoforms of NOX with NOX1, NOX2 and NOX4 expressed in multiple brain regions including the cerebral cortex, hippocampus, cerebellum, hypothalamus, midbrain and/or striatum (Hou et al, 2020). These NOX variants are the most prominent isoforms detected in a variety of brain cell types (Cahill-Smith and Li, 2014;Hou et al, 2020;Rastogi et al, 2016), with NOX2 the dominant form expressed by microglia, neurons, and astrocytes. Activation of NOX results in an increase of extracellular H 2 O 2 levels followed by H 2 O 2 entry into the cells via aquaporins (Bienert and Chaumont, 2014).…”

Section: The Cytoplasmic Antioxidant Systemmentioning

confidence: 99%

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Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

Zilberter

Zilberter²

2020

eNeuro

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The ketogenic diet (KD) has been successfully used for a century for treating refractory epilepsy and is currently seen as one of the few viable approaches to the treatment of a plethora of metabolic and neurodegenerative diseases. Empirical evidence notwithstanding, there is still no universal understanding of KD mechanism(s). An important fact is that the brain is capable of using ketone bodies for fuel. Another critical point is that glucose’s functions span beyond its role as an energy substrate, and in most of these functions, glucose is irreplaceable. By acting as a supplementary fuel, ketone bodies may free up glucose for its other crucial and exclusive function. We propose that this glucose-sparing effect of ketone bodies may underlie the effectiveness of KD in epilepsy and major neurodegenerative diseases, which are all characterized by brain glucose hypometabolism.

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Section: The Cytoplasmic Antioxidant Systemmentioning

confidence: 99%

Section: The Cytoplasmic Antioxidant Systemmentioning

confidence: 99%

Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

Zilberter

Zilberter²

2020

eNeuro

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“…We now show that Aβ also inhibits glucose utilization, thus establishing a vicious cycle of brain hypometabolism. (23,35,36,53,54). The close relationship between the levels of Aβ and NOX2 activity has also been well documented in multiple studies (22,38,(55)(56)(57)(58)(59).…”

Section: Discussionmentioning

confidence: 76%

“…NOX family of enzymes are transmembrane carriers that transport an electron from cytosolic NADPH to reduce oxygen to superoxide anion. There are seven isoforms of NOX with NOX1, NOX2 and NOX4 expressed in multiple brain regions including the cerebral cortex, hippocampus, cerebellum, hypothalamus, midbrain and/or striatum 23 , with NOX2 the dominant form expressed by microglia, neurons, and astrocytes [23][24][25] . Several lines of evidence including postmortem analyses of AD patients' cerebral cortices indicate that oxidative stress --particularly resulting from NOX2 activation --plays a significant role in the development of AD 20,23,[25][26][27] .…”

Section: Introductionmentioning

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

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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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“…In addition, activated microglia has recently been shown to be able to induce astrocytes into a neurotoxic A1 status by releasing TNFα, IL-1α and C1q to amplify neuronal damage [29]. Proin ammatory factors and reactive oxygen species (ROS) are considered to be critical to mediate neuroin ammatory damage since neutralization of proin ammatory factors or inhibition of ROS during neuroin ammation showed potent neuroprotection in a variety of neurodegeneration models [49]. Consistently, in this study, elevated astroglial activation, production of proin ammatory cytokine and oxidative stress were observed in rotenone-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Zhang

Hou

et al. 2020

Preprint

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BackgroundCognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the life quality of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by over-activated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using rotenone-induced mouse PD model. Methods: To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by morris water maze, objective recognition and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation and apoptosis were determined by immunohistochemistry, Western blot or immunofluorescence staining. The gene expressions of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. ResultsRotenone dose-dependently induced cognitive deficits in mice by showing decreased abilities of novel objective recognition, passive avoidance, as well as morris water maze performance compared with vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. Time course study revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 or minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in combined PLX3397 or minocycline and rotenone-treated mice compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. ConclusionsTaken together, our findings suggested that microglial activation contributed to cognitive impairments in rotenone-induced mouse PD model via neuroinflammation, oxidative stress and apoptosis, providing novel insight for the immunopathogensis of cognitive deficits in PD.

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Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Neurodegenerative Diseases: Mechanisms and Therapy

Cited by 30 publications

References 191 publications

Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

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

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

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