Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models

doi:10.1016/J.NEUROBIOLAGING.2012.12.005

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Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models

Journal Article•DOI•

Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models

Bing Gong¹, Yong Pan¹, Prashant Vempati¹, Wei Zhao¹, Lindsay Knable¹, Lap Ho¹, Jun Wang¹, Magdalena Sastre², Kenjiro Ono¹, Anthony A. Sauve³, Giulio Maria Pasinetti⁴, Giulio Maria Pasinetti¹ - Show less +8 more•Institutions (4)

Icahn School of Medicine at Mount Sinai¹, Imperial College London², Cornell University³, Veterans Health Administration⁴

01 Jun 2013-Neurobiology of Aging (Elsevier)-Vol. 34, Iss: 6, pp 1581-1588

TL;DR: The studies suggest that dietary treatment with NR might benefit AD cognitive function and synaptic plasticity, in part by promoting PGC-1α-mediated BACE1 ubiquitination and degradation, thus preventing Aβ production in the brain.

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About: This article is published in Neurobiology of Aging.The article was published on 2013-06-01 and is currently open access. It has received 281 citations till now. The article focuses on the topics: Nicotinamide riboside & NAD+ kinase.

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Journal Article•DOI•

NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus.

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Carles Cantó¹, Keir J. Menzies², Johan Auwerx²•Institutions (2)

Nestlé¹, École Polytechnique Fédérale de Lausanne²

07 Jul 2015-Cell Metabolism

TL;DR: This review summarizes how NAD(+) metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited.

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1,061 citations

Cites background from "Nicotinamide riboside restores cogn..."

...Additionally, NR has been shown to improve the AD phenotype via PGC-1a-mediated b-secretase (BACE1) degradation and the induction of mitochondrial biogenesis (Gong et al., 2013)....
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Journal Article•DOI•

NAD+ and sirtuins in aging and disease

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Shin-ichiro Imai¹, Leonard Guarente²•Institutions (2)

Washington University in St. Louis¹, Massachusetts Institute of Technology²

01 Aug 2014-Trends in Cell Biology

TL;DR: The combination of sirtuin activation and NAD(+) intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide.

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907 citations

Journal Article•DOI•

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States.

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Mark P. Mattson¹, Mark P. Mattson², Thiruma V. Arumugam³•Institutions (3)

Johns Hopkins University School of Medicine¹, National Institutes of Health², National University of Singapore³

05 Jun 2018-Cell Metabolism

TL;DR: An overview of the cellular and molecular biology of brain aging, how those processes interface with disease-specific neurodegenerative pathways, and how metabolic states influence brain health is provided.

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586 citations

Cites background or methods from "Nicotinamide riboside restores cogn..."

...…bolster mitochondrial function and SIRT3 activity by administration of 1188 Cell Metabolism 27, June 5, 2018 ketone esters or the NAD+ precursor nicotinamide riboside, both of which have been demonstrated to be beneficial in AD models (Gong et al., 2013; Kashiwaya et al., 2013; Hou et al., 2018)....
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...1188 Cell Metabolism 27, June 5, 2018 ketone esters or the NAD precursor nicotinamide riboside, both of which have been demonstrated to be beneficial in AD models (Gong et al., 2013; Kashiwaya et al., 2013; Hou et al., 2018)....
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Journal Article•DOI•

NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR

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Jun Yoshino¹, Joseph A. Baur², Shin-ichiro Imai³, Shin-ichiro Imai¹•Institutions (3)

Washington University in St. Louis¹, University of Pennsylvania², Japan Agency for Medical Research and Development³

14 Dec 2017-Cell Metabolism

TL;DR: A comprehensive concept that connects NAD+ metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health.

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528 citations

Cites background from "Nicotinamide riboside restores cogn..."

...One of the first studies to examine the effects of NR in vivo revealed a striking improvement in the progression of Alzheimer’s disease pathology in the Tg2576 model of the disease (Gong et al., 2013)....
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...…et al., 2012 Tg2576 mice (Alzheimer’s disease model, C57BL/6 background) unspecified 250 mg/kg (diet) 3 months slowed cognitive decline Gong et al., 2013 ‘‘Deletor’’ mice (Twinkle mutant causing mitochondrial myopathy, C57BL/6 background) male 400 mg/kg (diet) 4 months pre- or…...
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Journal Article•DOI•

Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds.

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Michael Bonkowski¹, David A. Sinclair², David A. Sinclair¹•Institutions (2)

Harvard University¹, University of New South Wales²

01 Nov 2016-Nature Reviews Molecular Cell Biology

TL;DR: The sirtuins (SIRT1-7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing as discussed by the authors.

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Abstract: The sirtuins (SIRT1-7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with sirtuin-activating compounds (STACs) such as resveratrol and SRT2104 or with NAD+ precursors, have improved organ function, physical endurance, disease resistance and longevity. Trials in non-human primates and in humans have indicated that STACs may be safe and effective in treating inflammatory and metabolic disorders, among others. These advances have demonstrated that it is possible to rationally design molecules that can alleviate multiple diseases and possibly extend lifespan in humans.

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526 citations

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References

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Open Access

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Journal Article•DOI•

Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice

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Karen Hsiao¹, Paul F. Chapman², Steven P. Nilsen¹, Chris Eckman³, Yasuo Harigaya³, Steven G. Younkin³, Fusheng Yang⁴, Greg M. Cole⁴ - Show less +4 more•Institutions (4)

University of Minnesota¹, Cardiff University², Mayo Clinic³, University of California, Los Angeles⁴

04 Oct 1996-Science

TL;DR: Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a Lys670 → Asn, Met671 → Leu mutation had normal learning and memory but showed impairment by 9 to 10 months of age.

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Abstract: Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.

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4,327 citations

"Nicotinamide riboside restores cogn..." refers methods in this paper

...PGC-1a To assess if NR has any protective effects on cognitive function as we proposed, we first treated Tg2576 AD transgenic (APP) mice (Hsiao et al., 1996) (7e8-month-old) with 250 mg/kg/day of NR (equivalent to 1300 mg/kg/day in the human) for 3 months via drinking water....
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...To assess if NR has any protective effects on cognitive function as we proposed, we first treated Tg2576 AD transgenic (APP) mice (Hsiao et al., 1996) (7e8-month-old) with 250 mg/kg/day of NR (equivalent to 1300 mg/kg/day in the human) for 3 months via...
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Journal Article•DOI•

Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.

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Joseph T. Rodgers¹, Carlos Lerin¹, Wilhelm Haas², Steven P. Gygi², Bruce M. Spiegelman², Pere Puigserver¹ - Show less +2 more•Institutions (2)

Johns Hopkins University School of Medicine¹, Harvard University²

03 Mar 2005-Nature

TL;DR: It is shown that the Sir2 homologue, SIRT1 controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α, and this findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.

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Abstract: Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1--which modulates ageing in several species--controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1alpha. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.

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2,841 citations

Journal Article•DOI•

Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study 'recognition memory'

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Rick A. Bevins¹, Joyce Besheer²•Institutions (2)

University of Nebraska–Lincoln¹, University of North Carolina at Chapel Hill²

01 Oct 2006-Nature Protocols

TL;DR: The object-recognition task has been used to study mutant mice, aging deficits, early developmental influences, nootropic manipulations, teratological drug exposure and novelty seeking.

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Abstract: Rats and mice have a tendency to interact more with a novel object than with a familiar object. This tendency has been used by behavioral pharmacologists and neuroscientists to study learning and memory. A popular protocol for such research is the object-recognition task. Animals are first placed in an apparatus and allowed to explore an object. After a prescribed interval, the animal is returned to the apparatus, which now contains the familiar object and a novel object. Object recognition is distinguished by more time spent interacting with the novel object. Although the exact processes that underlie this 'recognition memory' requires further elucidation, this method has been used to study mutant mice, aging deficits, early developmental influences, nootropic manipulations, teratological drug exposure and novelty seeking.

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1,029 citations

"Nicotinamide riboside restores cogn..." refers background in this paper

...After a certain interval, the mousewas returned to the apparatus, which contained the familiar object and a novel object (Bevins and Besheer, 2006)....
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Journal Article•DOI•

SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.

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Dohoon Kim¹, Dohoon Kim², Minh Dang Nguyen¹, Matthew M. Dobbin², Andre Fischer², Farahnaz Sananbenesi², Joseph T. Rodgers³, Joseph T. Rodgers¹, Ivana Delalle², Joseph A. Baur¹, Guangchao Sui¹, Sean M. Armour¹, Pere Puigserver¹, Pere Puigserver³, David A. Sinclair¹, Li-Huei Tsai² - Show less +12 more•Institutions (3)

Harvard University¹, Massachusetts Institute of Technology², Johns Hopkins University School of Medicine³

11 Jul 2007-The EMBO Journal

TL;DR: It is reported that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults, and provides a promising avenue for therapeutic intervention.

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Abstract: A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.

...read moreread less

1,013 citations

"Nicotinamide riboside restores cogn..." refers background in this paper

...Recent studies have shown that the activation of NAD expression has been linked with a decrease in the amyloid toxicity in Alzheimer’s disease (AD) animal models (Kim et al., 2007; Qin et al., 2006), in which it might relate to the interactions with the expression of peroxisome proliferator-activated receptor-g coactivator 1 (PGC)-1a (Nemoto et al....
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...…have shown that the activation of NAD expression has been linked with a decrease in the amyloid toxicity in Alzheimer’s disease (AD) animal models (Kim et al., 2007; Qin et al., 2006), in which it might relate to the interactions with the expression of peroxisome proliferator-activated…...
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Journal Article•DOI•

SIRT1 Functionally Interacts with the Metabolic Regulator and Transcriptional Coactivator PGC-1α

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Shino Nemoto¹, Maria M. Fergusson¹, Toren Finkel¹•Institutions (1)

National Institutes of Health¹

22 Apr 2005-Journal of Biological Chemistry

TL;DR: The cellular effects of overexpression of SIRT1, the closest mammalian ortholog of Sir2, are examined and it is demonstrated that SIRT 1 catalyzes PGC-1α deacetylation both in vitro and in vivo.

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974 citations

"Nicotinamide riboside restores cogn..." refers background in this paper

..., 2006), in which it might relate to the interactions with the expression of peroxisome proliferator-activated receptor-g coactivator 1 (PGC)-1a (Nemoto et al., 2005) and through the activation of neuronal NAD-dependent deacetylase sirtuin-1 (SIRT1) activation (Qin et al....
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...…al., 2006), in which it might relate to the interactions with the expression of peroxisome proliferator-activated receptor-g coactivator 1 (PGC)-1a (Nemoto et al., 2005) and through the activation of neuronal NAD-dependent deacetylase sirtuin-1 (SIRT1) activation (Qin et al., 2006; Rodgers et…...
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