Benefits of Enhancing Nicotinamide Adenine Dinucleotide Levels in Damaged or Diseased Nerve Cells

Pieper, Andrew A.; McKnight, Steven L.

doi:10.1101/sqb.2018.83.037622

Cited by 14 publications

(16 citation statements)

References 113 publications

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“…Thus, multiple lines of evidence converge to show that reducing neuronal ac-tau is a successful therapeutic approach for treating TBI, whether that is through inhibiting acetylation with already existing drugs that could be repurposed for TBI, or through enhancing deacetylation through a drug to emerge from the P7C3 series of molecules. Other strategies to preserve NAD + after injury, such as pharmacologic inhibitors of the NAD hydrolase SARMI, might be similarly effective (Pieper and McKnight, 2018;Hughes et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…NAD + levels under conditions of neuronal stress can also be preserved by treatment with the aminopropyl carbazole P7C3-A20 (Pieper et al, 2010;Wang et al, 2014;Pieper and McKnight, 2018). Here, P7C3-A20, administered daily beginning 24 h after brain injury, preserved brain NAD + levels (Figure 5A) and prevented accumulation of ac-tau (Figure 5B).…”

Section: Elevating Nad + Enhances Sirtl Activity and Blocks Injury-induced Tau Acetylation Neurodegeneration And Neurobehavioral Impairmementioning

confidence: 91%

“…Next, we tested the complementary approach of increasing Sirtl -mediated tau deacetylation. Sirtl activity is dependent on nicotinamide adenine dinucleotide (NAD + ), and high expression of the Ube4b/nicotinamide mononucleotide adenylyltransferase 1 fusion protein in Wld S mice results in constitutively elevated NAD* levels that protect these animals from axonal degeneration and neurobehavioral impairment after brain injury (Pieper and McKnight, 2018;Yin et al, 2016). Here, Wld S mice were also completely protected from injury-induced increases in ac-tau (Figure 4A) and AIS degradation throughout the brain (Figure 4B), which correlated with complete protection from tau mislocalization as well (Figures 4C and S5I).…”

Section: Elevating Nad + Enhances Sirtl Activity and Blocks Injury-induced Tau Acetylation Neurodegeneration And Neurobehavioral Impairmementioning

confidence: 99%

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Reducing acetylated tau is neuroprotective in brain injury

Shin

Vázquez‐Rosa

Koh

et al. 2021

Cell

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114

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Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimers disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuinl deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuinl all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

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Section: Discussionmentioning

confidence: 99%

Section: Elevating Nad + Enhances Sirtl Activity and Blocks Injury-induced Tau Acetylation Neurodegeneration And Neurobehavioral Impairmementioning

confidence: 91%

Section: Elevating Nad + Enhances Sirtl Activity and Blocks Injury-induced Tau Acetylation Neurodegeneration And Neurobehavioral Impairmementioning

confidence: 99%

See 1 more Smart Citation

Reducing acetylated tau is neuroprotective in brain injury

Shin

Vázquez‐Rosa

Koh

et al. 2021

Cell

Self Cite

114

View full text Add to dashboard Cite

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“…While NAD + levels appear to be relatively stable in cells, NAD + homeostasis is a very dynamic process. Maintaining NAD + homeostasis requires a balance between NAD + There is growing evidence that NAD + can have an impact on neurodegeneration [6][7][8]. NAD + and NAD + biosynthetic enzymes are essential for neuronal health and survival, and this has led to NAD + being investigated for a possible role in different neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, with findings suggesting NAD + -or NAD + -synthesizing enzymes could be involved in pathological development or therapeutic strategies [6,7].…”

Section: Cellular Nad + Homeostasismentioning

confidence: 99%

NAD+ Metabolism and Diseases with Motor Dysfunction

Lundt

Ding

2021

Genes

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Neurodegenerative diseases result in the progressive deterioration of the nervous system, with motor and cognitive impairments being the two most observable problems. Motor dysfunction could be caused by motor neuron diseases (MNDs) characterized by the loss of motor neurons, such as amyotrophic lateral sclerosis and Charcot–Marie–Tooth disease, or other neurodegenerative diseases with the destruction of brain areas that affect movement, such as Parkinson’s disease and Huntington’s disease. Nicotinamide adenine dinucleotide (NAD+) is one of the most abundant metabolites in the human body and is involved with numerous cellular processes, including energy metabolism, circadian clock, and DNA repair. NAD+ can be reversibly oxidized-reduced or directly consumed by NAD+-dependent proteins. NAD+ is synthesized in cells via three different paths: the de novo, Preiss–Handler, or NAD+ salvage pathways, with the salvage pathway being the primary producer of NAD+ in mammalian cells. NAD+ metabolism is being investigated for a role in the development of neurodegenerative diseases. In this review, we discuss cellular NAD+ homeostasis, looking at NAD+ biosynthesis and consumption, with a focus on the NAD+ salvage pathway. Then, we examine the research, including human clinical trials, focused on the involvement of NAD+ in MNDs and other neurodegenerative diseases with motor dysfunction.

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“…Recent report show that administration of P7C3 in animal models and tissue cultures enhance the enzymatic activity of Nampt, the key rate‐limiting enzyme in the NAD salvage pathway from nicotinamide 35 . Therefore, we tested the P7C3 specificity of Nampt activity using enzyme assay with or without P7C (Figure 8A).…”

Section: Resultsmentioning

confidence: 99%

Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators

Manickam

Tur

Badole

et al. 2022

J cachexia sarcopenia muscle

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Background Nicotinamide phosphoribosyltransferase (Nampt), a key enzyme in NAD salvage pathway is decreased in metabolic diseases, and its precise role in skeletal muscle function is not known. We tested the hypothesis, Nampt activation by P7C3 (3,6-dibromo-α-[(phenylamino)methyl]-9H-carbazol-9-ethanol) ameliorates diabetes and muscle function. Methods We assessed the functional, morphometric, biochemical, and molecular effects of P7C3 treatment in skeletal muscle of type 2 diabetic (db/db) mice. Nampt +/À mice were utilized to test the specificity of P7C3. Results Insulin resistance increased 1.6-fold in diabetic mice compared with wild-type mice and after 4 weeks treatment with P7C3 rescued diabetes (P < 0.05). In the db-P7C3 mice fasting blood glucose levels decreased to 0.96-fold compared with C57Bl/6J wild-type naïve control mice. The insulin and glucose tolerance tests blood glucose levels were decreased to 0.6-fold and 0.54-folds, respectively, at 120 min along with an increase in insulin secretion (1.76-fold) and pancreatic β-cells (3.92-fold) in db-P7C3 mice. The fore-limb and hind-limb grip strengths were increased to 1.13-fold and 1.17-fold, respectively, together with a 14.2-fold increase in voluntary running wheel distance in db-P7C3 mice. P7C3 treatment resulted in a 1.4-fold and 7.1-fold increase in medium-sized and larger-sized myofibres cross-sectional area, with a concomitant 0.5-fold decrease in smaller-sized myofibres of tibialis anterior (TA) muscle. The transmission electron microscopy images also displayed a 1.67-fold increase in myofibre diameter of extensor digitorum longus muscle along with 2.9-fold decrease in mitochondrial area in db-P7C3 mice compared with db-Veh mice. The number of SDH positive myofibres were increased to 1.74-fold in db-P7C3 TA muscles. The gastrocnemius and TA muscles displayed a decrease in slow oxidative myosin heavy chain type1 (MyHC1) myofibres expression (0.46-fold) and immunostaining (6.4-fold), respectively. qPCR analysis displayed a 2.9-fold and 1.3-fold increase in Pdk4 and Cpt1, and 0.55-fold and 0.59-fold decrease in Fgf21 and 16S in db-P7C3 mice. There was also a 3.3-fold and 1.9-fold increase in Fabp1 and CD36 in db-Veh mice. RNA-seq differential gene expression volcano plot displayed 1415 genes to be up-regulated and 1726 genes down-regulated (P < 0.05) in db-P7C3 mice. There was 1.02-fold increase in serum HDL, and 0.9-fold decrease in low-density lipoprotein/very low-density lipoprotein ratio in db-P7C3 mice. Lipid profiling of gastrocnemius muscle displayed a decrease in inflammatory lipid mediators n-6; AA (0.83-fold), and n-3; DHA (0.69-fold) and EPA (0.81-fold), and a 0.66-fold decrease in endocannabinoid 2-AG and 2.0-fold increase in AEA in db-P7C3 mice. Conclusions Overall, we demonstrate that P7C3 activates Nampt, improves type 2 diabetes and skeletal muscle function in db/db mice.

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Benefits of Enhancing Nicotinamide Adenine Dinucleotide Levels in Damaged or Diseased Nerve Cells

Cited by 14 publications

References 113 publications

Reducing acetylated tau is neuroprotective in brain injury

Reducing acetylated tau is neuroprotective in brain injury

NAD+ Metabolism and Diseases with Motor Dysfunction

Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators

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