Reversibility of Age-related Oxidized Free NADH Redox States in Alzheimer’s Disease Neurons by Imposed External Cys/CySS Redox Shifts

Abstract Redox systems including extracellular cysteine/cystine (Cys/CySS), intracellular glutathione/oxidized glutathione (GSH/GSSG) and nicotinamide adenine dinucleotide reduced/oxidized forms (NADH/NAD+) are critical for maintaining redox homeostasis. Aging as a major risk factor for Alzheimer’s...

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Autores principales:	Yue Dong, Sara Sameni, Michelle A. Digman, Gregory J. Brewer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3d994a935b6545bf8db9f5135a0b2f0d
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spelling	oai:doaj.org-article:3d994a935b6545bf8db9f5135a0b2f0d2021-12-02T15:09:37ZReversibility of Age-related Oxidized Free NADH Redox States in Alzheimer’s Disease Neurons by Imposed External Cys/CySS Redox Shifts10.1038/s41598-019-47582-x2045-2322https://doaj.org/article/3d994a935b6545bf8db9f5135a0b2f0d2019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-47582-xhttps://doaj.org/toc/2045-2322Abstract Redox systems including extracellular cysteine/cystine (Cys/CySS), intracellular glutathione/oxidized glutathione (GSH/GSSG) and nicotinamide adenine dinucleotide reduced/oxidized forms (NADH/NAD+) are critical for maintaining redox homeostasis. Aging as a major risk factor for Alzheimer’s disease (AD) is associated with oxidative shifts, decreases in anti-oxidant protection and dysfunction of mitochondria. Here, we examined the flexibility of mitochondrial-specific free NADH in live neurons from non-transgenic (NTg) or triple transgenic AD-like mice (3xTg-AD) of different ages under an imposed extracellular Cys/CySS oxidative or reductive condition. We used phasor fluorescence lifetime imaging microscopy (FLIM) to distinguish free and bound NADH in mitochondria, nuclei and cytoplasm. Under an external oxidative stress, a lower capacity for maintaining mitochondrial free NADH levels was found in old compared to young neurons and a further decline with genetic load. Remarkably, an imposed Cys/CySS reductive state rejuvenated the mitochondrial free NADH levels of old NTg neurons by 71% and old 3xTg-AD neurons by 89% to levels corresponding to the young neurons. Using FLIM as a non-invasive approach, we were able to measure the reversibility of aging subcellular free NADH levels in live neurons. Our results suggest a potential reductive treatment to reverse the loss of free NADH in old and Alzheimer’s neurons.Yue DongSara SameniMichelle A. DigmanGregory J. BrewerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-13 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yue Dong Sara Sameni Michelle A. Digman Gregory J. Brewer Reversibility of Age-related Oxidized Free NADH Redox States in Alzheimer’s Disease Neurons by Imposed External Cys/CySS Redox Shifts
description	Abstract Redox systems including extracellular cysteine/cystine (Cys/CySS), intracellular glutathione/oxidized glutathione (GSH/GSSG) and nicotinamide adenine dinucleotide reduced/oxidized forms (NADH/NAD+) are critical for maintaining redox homeostasis. Aging as a major risk factor for Alzheimer’s disease (AD) is associated with oxidative shifts, decreases in anti-oxidant protection and dysfunction of mitochondria. Here, we examined the flexibility of mitochondrial-specific free NADH in live neurons from non-transgenic (NTg) or triple transgenic AD-like mice (3xTg-AD) of different ages under an imposed extracellular Cys/CySS oxidative or reductive condition. We used phasor fluorescence lifetime imaging microscopy (FLIM) to distinguish free and bound NADH in mitochondria, nuclei and cytoplasm. Under an external oxidative stress, a lower capacity for maintaining mitochondrial free NADH levels was found in old compared to young neurons and a further decline with genetic load. Remarkably, an imposed Cys/CySS reductive state rejuvenated the mitochondrial free NADH levels of old NTg neurons by 71% and old 3xTg-AD neurons by 89% to levels corresponding to the young neurons. Using FLIM as a non-invasive approach, we were able to measure the reversibility of aging subcellular free NADH levels in live neurons. Our results suggest a potential reductive treatment to reverse the loss of free NADH in old and Alzheimer’s neurons.
format	article
author	Yue Dong Sara Sameni Michelle A. Digman Gregory J. Brewer
author_facet	Yue Dong Sara Sameni Michelle A. Digman Gregory J. Brewer
author_sort	Yue Dong
title	Reversibility of Age-related Oxidized Free NADH Redox States in Alzheimer’s Disease Neurons by Imposed External Cys/CySS Redox Shifts
title_short	Reversibility of Age-related Oxidized Free NADH Redox States in Alzheimer’s Disease Neurons by Imposed External Cys/CySS Redox Shifts
title_full	Reversibility of Age-related Oxidized Free NADH Redox States in Alzheimer’s Disease Neurons by Imposed External Cys/CySS Redox Shifts
title_fullStr	Reversibility of Age-related Oxidized Free NADH Redox States in Alzheimer’s Disease Neurons by Imposed External Cys/CySS Redox Shifts
title_full_unstemmed	Reversibility of Age-related Oxidized Free NADH Redox States in Alzheimer’s Disease Neurons by Imposed External Cys/CySS Redox Shifts
title_sort	reversibility of age-related oxidized free nadh redox states in alzheimer’s disease neurons by imposed external cys/cyss redox shifts
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/3d994a935b6545bf8db9f5135a0b2f0d
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Reversibility of Age-related Oxidized Free NADH Redox States in Alzheimer’s Disease Neurons by Imposed External Cys/CySS Redox Shifts

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