The plasma membrane redox system is impaired by amyloid β-peptide and in the hippocampus and cerebral cortex of 3xTgAD mice

Hyun, Dong Hoon; Mughal, Mohamed R.; Yang, Hyunwon; Lee, Ji Hyun; Ko, Eun Joo; Hunt, Nicole; Cabo, Rafael de; Mattson, Mark P.

doi:10.1016/j.expneurol.2010.07.020

Cited by 39 publications

(22 citation statements)

References 53 publications

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“…Other reports indicate that altered NQO1 expression is related to the pathogenesis of Alzheimer°s disease (AD) [25], [26], and suggest a potential neuroprotective role for NQO1 in diseases involving metabolic and oxidative stresses including AD [27]. NQO1 can protect cultured cells against toxic insults by regulating PMRS activity [28].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Function in Human Neuroblastoma Cells Is Up-Regulated and Protected by NQO1, a Plasma Membrane Redox Enzyme

Kim

et al. 2013

PLoS ONE

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BackgroundRecent findings suggest that NADH-dependent enzymes of the plasma membrane redox system (PMRS) play roles in the maintenance of cell bioenergetics and oxidative state. Neurons and tumor cells exhibit differential vulnerability to oxidative and metabolic stress, with important implications for the development of therapeutic interventions that promote either cell survival (neurons) or death (cancer cells).Methods and FindingsHere we used human neuroblastoma cells with low or high levels of the PMRS enzyme NADH-quinone oxidoreductase 1 (NQO1) to investigate how the PMRS modulates mitochondrial functions and cell survival. Cells with elevated NQO1 levels exhibited higher levels of oxygen consumption and ATP production, and lower production of reactive oxygen species. Cells overexpressing NQO1 were more resistant to being damaged by the mitochondrial toxins rotenone and antimycin A, and exhibited less oxidative/nitrative damage and less apoptotic cell death. Cells with basal levels of NQO1 resulted in increased oxidative damage to proteins and cellular vulnerability to mitochondrial toxins. Thus, mitochondrial functions are enhanced and oxidative stress is reduced as a result of elevated PMRS activity, enabling cells to maintain redox homeostasis under conditions of metabolic and energetic stress.ConclusionThese findings suggest that NQO1 is a potential target for the development of therapeutic agents for either preventing neuronal degeneration or promoting the death of neural tumor cells.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial Function in Human Neuroblastoma Cells Is Up-Regulated and Protected by NQO1, a Plasma Membrane Redox Enzyme

Kim

et al. 2013

PLoS ONE

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“…We showed that administration of coenzyme Q10 in the diet to Tg19959 mice, which have two mutations in the AβPP gene, significantly reduced oxidative damage to proteins, the numbers of amyloid plaques, amyloid plaque burden, amyloid-β 1-42 levels, and it improved performance on the Morris water maze test [13]. A recent report showed that in addition to increased oxidative stress, levels of coenzyme Q10 were reduced in transgenic AD mice expressing both AβPP and tau mutations [41]. However, it is not known whether coenzyme Q10 can affect tau induced pathology.…”

Section: Discussionmentioning

confidence: 99%

Behavioral Improvement after Chronic Administration of Coenzyme Q10 in P301S Transgenic Mice

Elipenahli

Stack

Jainuddin

et al. 2012

JAD

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Coenzyme Q10 is a key component of the electron transport chain which plays an essential role in ATP production and also has antioxidant effects. Neuroprotective effects of coenzyme Q10 have been reported in both in vitro and in vivo models of neurodegenerative diseases. However, its effects have not been studied in cells or in animals with tau induced pathology. In this report, we administered coenzyme Q10 to transgenic mice with the P301S tau mutation, which causes fronto-temporal dementia in man. These mice develop tau hyperphosphorylation and neurofibrillary tangles in the brain. Coenzyme Q10 improved survival and behavioral deficits in the P301S mice. There was a modest reduction in phosphorylated tau in the cortex of P301S mice. We also examined the effects of coenzyme Q10 treatment on the electron transport chain enzymes, the mitochondrial antioxidant enzymes, and the tricarboxylic acid cycle. There was a significant increase in complex I activity and protein levels, and a reduction in lipid peroxidation. Our data show that coenzyme Q10 significantly improved behavioral deficits and survival in transgenic mice with the P301S tau mutation, upregulated key enzymes of the electron transport chain, and reduced oxidative stress.

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“…Healthy neurons respond to the oxidative stress triggered by excitatory synaptic activity by activating the transcription factors NF-κB and Nrf2 which, in turn induce the expression of SOD2 and HO1, respectively 81,82 . Another defense against oxidative stress that is adversely impacted in aging and AD is the plasma membrane redox system, which includes the enzymes NADH-quinone oxidoreductase 1 (NQO1), NADH-ferrocyanide reductase, NADH-coenzyme Q10 reductase, and NADH-cytochrome c reductase 83, 84 .…”

Section: Compromised Adaptive Cellular Stress Responses and Ilodmentioning

confidence: 99%

Late-onset dementia: a mosaic of prototypical pathologies modifiable by diet and lifestyle

Mattson

2015

npj Aging Mech Dis

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Idiopathic late-onset dementia (ILOD) describes impairments of memory, reasoning and/or social abilities in the elderly that compromise their daily functioning. Dementia occurs in several major prototypical neurodegenerative disorders that are currently defined by neuropathological criteria, most notably Alzheimer’s disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and hippocampal sclerosis of aging (HSA). However, people who die with ILOD commonly exhibit mixed pathologies that vary within and between brain regions. Indeed, many patients diagnosed with probable AD exhibit only modest amounts of disease-defining amyloid β-peptide plaques and p-Tau tangles, and may have features of FTD (TDP-43 inclusions), Parkinson’s disease (α-synuclein accumulation), HSA and vascular lesions. Here I argue that this ‘mosaic neuropathological landscape’ is the result of commonalities in aging-related processes that render neurons vulnerable to the entire spectrum of ILODs. In this view, all ILODs involve deficits in neuronal energy metabolism, neurotrophic signaling and adaptive cellular stress responses, and associated dysregulation of neuronal calcium handling and autophagy. Although this mosaic of neuropathologies and underlying mechanisms poses major hurdles for development of disease-specific therapeutic interventions, it also suggests that certain interventions would be beneficial for all ILODs. Indeed, emerging evidence suggests that the brain can be protected against ILOD by lifelong intermittent physiological challenges including exercise, energy restriction and intellectual endeavors; these interventions enhance cellular stress resistance and facilitate neuroplasticity. There is also therapeutic potential for interventions that bolster neuronal bioenergetics and/or activate one or more adaptive cellular stress response pathways in brain cells. A wider appreciation that all ILODs share age-related cellular and molecular alterations upstream of aggregated protein lesions, and that these upstream events can be mitigated, may lead to implementation of novel intervention strategies aimed at reversing the rising tide of ILODs.

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The plasma membrane redox system is impaired by amyloid β-peptide and in the hippocampus and cerebral cortex of 3xTgAD mice

Cited by 39 publications

References 53 publications

Mitochondrial Function in Human Neuroblastoma Cells Is Up-Regulated and Protected by NQO1, a Plasma Membrane Redox Enzyme

Mitochondrial Function in Human Neuroblastoma Cells Is Up-Regulated and Protected by NQO1, a Plasma Membrane Redox Enzyme

Behavioral Improvement after Chronic Administration of Coenzyme Q10 in P301S Transgenic Mice

Late-onset dementia: a mosaic of prototypical pathologies modifiable by diet and lifestyle

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