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MetaboLights MTBLS368 - GNPS "Nicotinamide Riboside is Uniquely Bioavailable in People and Mice"

ABSTRACT: This data set was downloaded from MetaboLights (http://www.ebi.ac.uk/metabolights/) accession number MTBLS368 Abstract:"Nicotinamide riboside (NR) is in wide use as an NAD+ precursor vitamin. Here we conducted experiments to determine the time and dose-dependent effects of NR on blood, liver and heart NAD+ metabolism in people and mice. We report that human blood cell NAD+ can rise as much as 2.7-fold with a single dose of NR, that NR elevates mouse hepatic NAD+ with distinct and superior pharmacokinetics to those of nicotinic acid (NA) and nicotinamide (Nam), and that single doses of 100, 300, and 1000 mg of NR provide a dose-dependent increase in the blood cell NAD+ metabolome in the first clinical trial of NR pharmacokinetics. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for conversion of NR to NAD+, is formed from NR and that the rise in NAAD is a highly sensitive biomarker of effective NAD+ supplementation."

INSTRUMENT(S): ACQUITY TQD (Waters)

ORGANISM(S): Blank Homo Sapiens Reference Compound Mus Musculus

SUBMITTER: Brenner

PROVIDER: MSV000082797 | GNPS | Tue Aug 07 16:42:00 BST 2018

REPOSITORIES: GNPS

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Project description:Alzheimer's disease (AD) is a severe neurodegenerative disorder. Clinical trials to identify agents to treat AD have failed, and its underlying molecular pathology and etiology remain elusive. Neuroinflammation is thought to play a key role in the progression of AD. Emerging evidence has identified lower Nicotinamide adenine dinucleotide (NAD+) levels as a major factor in neurodegeneration, especially in AD. NAD+ is an important metabolite in all human cells, as it is at the convergence of many central processes in cellular and mitochondrial maintenance, including DNA repair and mitophagy (the degradation of damaged mitochondria). Our previous work found that treatment of 3xTgAD mice with an NAD+ precursor, nicotinamide riboside (NR), can improve key AD features including tau phosphorylation and learning deficits in mice. Here we used the APP/PS1 AD mouse model to interrogate the effect of NR on neuroinflammation. Microarray analysis revealed major changes in pathways and genes associated with inflammation and the APP/PS1 mice had lower NAD+ levels than WT mice. Thus, seven months old mice were treated with NR for five months and their NAD+/NADH ratio increased. Brain neuroinflammation decreased as determined by decreased activation of astrocytes and microglia, decreased pro-inflammatory cytokines and chemokines in the brains of the APP/PS1 mice. NR decreased neuroinflammation by lowering the NLRP3 inflammasome and NF-κB pathways. NR also attenuated DNA damage and apoptosis in the AD mouse brains. NR dramatically decreased senescence in the hippocampus and cortex of AD mice, relative to controls. Recent studies suggest that cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) activation are associated with DNA damage and senescence. cGAS-STING was activated in AD mice and decreases after NR treatment. Suggesting that NR can diminish neuroinflammation and senescence through the cGAS-STING pathway. NR treatment also greatly improved cognition and synaptic function in the APP/PS1 mice. We propose that the cGAS-STING pathway should be evaluated as a potential novel therapeutic target in AD.

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MetaboLights MTBLS368 - GNPS "Nicotinamide Riboside is Uniquely Bioavailable in People and Mice"

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