Nicotinamide adenine dinucleotide (NAD) supplementation to repair the disabled mitochondria is a promising strategy for the treatment of Alzheimer’s disease (AD) and other dementia. Nicotinamide ribose (NR) is a safe NAD precursor with high oral bioavailability, and has beneficial effects on aging. Here, we applied NR supplied food (2.5 g/kg food) to APP/PS1 transgenic AD model mice and aged mice for 3 months. Cognitive function, locomotor activity and anxiety level were assessed by standard behavioral tests. The change of body weight, the activation of microglia and astrocytes, the accumulation of Aβ and the level of serum nicotinamide phosphoribosyltransferase (NAMPT) were determined for the evaluation of pathological processes. We found that NR supplementation improved the short-term spatial memory of aged mice, and the contextual fear memory of AD mice. Moreover, NR supplementation inhibited the activation of astrocytes and the elevation of serum NAMPT of aged mice. For AD model mice, NR supplementation inhibited the accumulation of Aβ and the migration of astrocyte to Aβ. In addition, NR supplementation inhibit the body weight gain of aged and APP/PS1 mice. Thus, NR has selective benefits for both AD and aged mice, and the oral uptake of NR can be used to prevent the progression of dementia.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Anderson RM, Hadjichrysanthou C, Evans S, Wong MM (2017) Why do so many clinical trials of therapies for Alzheimer's disease fail? Lancet 390(10110):2327–2329
Bachurin SO, Gavrilova SI, Samsonova A, Barreto GE, Aliev G (2018) Mild cognitive impairment due to Alzheimer disease: contemporary approaches to diagnostics and pharmacological intervention. Pharmacol Res 129:216–226
Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 277(47):45099–45107
Bogan KL, Brenner C (2008) Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr 28:115–130
Braidy N, Berg J, Clement J, Khorshidi F, Poljak A, Jayasena T, Grant R, Sachdev P (2018) Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases: rationale, biochemistry, pharmacokinetics, and outcomes. Antioxid Redox Signal. https://doi.org/10.1089/ars.2017.7269
Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J (2012) The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 15(6):838–847
Cummings J, Lee G, Ritter A, Zhong K (2018) Alzheimer's disease drug development pipeline: 2018. Alzheimers Dement (N Y) 4:195–214
de Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, Imai S, Seals DR (2016) Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15(3):522–530
Di Stefano M, Nascimento-Ferreira I, Orsomando G, Mori V, Gilley J, Brown R, Janeckova L, Vargas ME, Worrell LA, Loreto A, Tickle J, Patrick J, Webster JR, Marangoni M, Carpi FM, Pucciarelli S, Rossi F, Meng W, Sagasti A, Ribchester RR, Magni G, Coleman MP, Conforti L (2015) A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration. Cell Death Differ 22(5):731–742
Gesing J, Scheuermann K, Wagner IV, Loffler D, Friebe D, Kiess W, Schuster V, Korner A (2017) NAMPT serum levels are selectively elevated in acute infectious disease and in acute relapse of chronic inflammatory diseases in children. PLoS One 12(8):e0183027
Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, Wang J, Sastre M, Ono K, Sauve AA, Pasinetti GM (2013) Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging 34(6):1581–1588
Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, Zhang Y, Moritoh K, O'Connell JF, Baptiste BA, Stevnsner TV, Mattson MP, Bohr VA (2018) NAD(+) supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A 115(8):E1876–E1885
Imai S, Kiess W (2009) Therapeutic potential of SIRT1 and NAMPT-mediated NAD biosynthesis in type 2 diabetes. Front Biosci (Landmark Ed) 14:2983–2995
Johnson S, Imai SI (2018) NAD (+) biosynthesis, aging, and disease. F1000Res 7:132
Kirkland JB, Meyer-Ficca ML (2018) Niacin. Adv Food Nutr Res 83:83–149
Lagadec S, Rotureau L, Hemar A, Macrez N, Delcasso S, Jeantet Y, Cho YH (2012) Early temporal short-term memory deficits in double transgenic APP/PS1 mice. Neurobiol Aging 33(1):203. e201–203. e211
Lai W, Wu J, Zou X, Xie J, Zhang L, Zhao X, Zhao M, Wang Q, Ji J (2013) Secretome analyses of Abeta(1-42) stimulated hippocampal astrocytes reveal that CXCL10 is involved in astrocyte migration. J Proteome Res 12(2):832–843
Lao K, Ji N, Zhang X, Qiao W, Tang Z, Gou X (2018) Drug development for Alzheimer's disease: review. J Drug Target:1–10
Li C, Yan Y, Cheng J, Xiao G, Gu J, Zhang L, Yuan S, Wang J, Shen Y, Zhou YD (2016) Toll-like receptor 4 deficiency causes reduced exploratory behavior in mice under approach-avoidance conflict. Neurosci Bull 32(2):127–136
Li D, Zhang L, Huang X, Liu L, He Y, Xu L, Zhang Y, Zhao T, Wu L, Zhao Y, Wu K, Wu Y, Fan M, Zhu L (2017) WIP1 phosphatase plays a critical neuroprotective role in brain injury induced by high-altitude hypoxic inflammation. Neurosci Bull 33(3):292–298
Liu LY, Wang F, Zhang XY, Huang P, Lu YB, Wei EQ, Zhang WP (2012) Nicotinamide phosphoribosyltransferase may be involved in age-related brain diseases. PLoS One 7(10):e44933
Liu D, Pitta M, Jiang H, Lee JH, Zhang G, Chen X, Kawamoto EM, Mattson MP (2013) Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession. Neurobiol Aging 34(6):1564–1580
Long AN, Owens K, Schlappal AE, Kristian T, Fishman PS, Schuh RA (2015) Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer's disease-relevant murine model. BMC Neurol 15:19
Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR (2018) Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun 9(1):1286
Mendelsohn AR, Larrick JW (2017) The NAD+/PARP1/SIRT1 Axis in aging. Rejuvenation Res 20(3):244–247
Montecucco F, Cea M, Cagnetta A, Damonte P, Nahimana A, Ballestrero A, Del Rio A, Bruzzone S, Nencioni A (2013) Nicotinamide phosphoribosyltransferase as a target in inflammation- related disorders. Curr Top Med Chem 13(23):2930–2938
Moschen AR, Gerner RR, Tilg H (2010) Pre-B cell colony enhancing factor/NAMPT/visfatin in inflammation and obesity-related disorders. Curr Pharm Des 16(17):1913–1920
Mouchiroud L, Houtkooper RH, Auwerx J (2013) NAD(+) metabolism: a therapeutic target for age-related metabolic disease. Crit Rev Biochem Mol Biol 48(4):397–408
Murchison CF, Zhang XY, Zhang WP, Ouyang M, Lee A, Thomas SA (2004) A distinct role for norepinephrine in memory retrieval. Cell 117(1):131–143
Rappou E, Jukarainen S, Rinnankoski-Tuikka R, Kaye S, Heinonen S, Hakkarainen A, Lundbom J, Lundbom N, Saunavaara V, Rissanen A, Virtanen KA, Pirinen E, Pietilainen KH (2016) Weight loss is associated with increased NAD(+)/SIRT1 expression but reduced PARP activity in white adipose tissue. J Clin Endocrinol Metab 101(3):1263–1273
Ritter AM, Ames FQ, Otani F, de Oliveira RM, Cuman RK, Bersani-Amado CA (2014) Effects of anethole in nociception experimental models. Evid Based Complement Alternat Med 2014:345829
Ruan Q, Ruan J, Zhang W, Qian F, Yu Z (2018) Targeting NAD(+) degradation: the therapeutic potential of flavonoids for Alzheimer's disease and cognitive frailty. Pharmacol Res 128:345–358
Ryu D, Zhang H, Ropelle ER, Sorrentino V, Mazala DA, Mouchiroud L, Marshall PL, Campbell MD, Ali AS, Knowels GM, Bellemin S, Iyer SR, Wang X, Gariani K, Sauve AA, Canto C, Conley KE, Walter L, Lovering RM, Chin ER, Jasmin BJ, Marcinek DJ, Menzies KJ, Auwerx J (2016) NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci Transl Med 8(361):361ra139
Sato S, Solanas G, Peixoto FO, Bee L, Symeonidi A, Schmidt MS, Brenner C, Masri S, Benitah SA, Sassone-Corsi P (2017) Circadian reprogramming in the liver identifies metabolic pathways of aging. Cell 170(4):664–677 e611
Schneider L (2017) Alzheimer's disease and other dementias: update on research. Lancet Neurol 16(1):4–5
Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, Li Z, Abel ED, Migaud ME, Brenner C (2016a) Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 7:12948
Trammell SA, Yu L, Redpath P, Migaud ME, Brenner C (2016b) Nicotinamide riboside is a major NAD+ precursor vitamin in cow Milk. J Nutr 146(5):957–963
Vaur P, Brugg B, Mericskay M, Li Z, Schmidt MS, Vivien D, Orset C, Jacotot E, Brenner C, Duplus E (2017) Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. FASEB J 31(12):5440–5452
Wang X, Hu X, Yang Y, Takata T, Sakurai T (2016) Nicotinamide mononucleotide protects against beta-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res 1643:1–9
Xiao J, Huang Y, Li X, Li L, Yang T, Huang L, Yang L, Jiang H, Li H, Li F (2016) TNP-ATP is beneficial for treatment of neonatal hypoxia-induced Hypomyelination and cognitive decline. Neurosci Bull 32(1):99–107
Yan P, Bero AW, Cirrito JR, Xiao Q, Hu X, Wang Y, Gonzales E, Holtzman DM, Lee JM (2009) Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J Neurosci 29(34):10706–10714
Yang L, Shi LJ, Tang B, Han QQ, Yu J, Wu GC, Zhang YQ (2016) Opposite sex contact and isolation: a novel depression/anxiety model. Neurosci Bull 32(1):92–98
Yoshino J, Baur JA, Imai SI (2018) NAD(+) intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab 27(3):513–528
Zhang M, Ying W (2018) NAD(+) deficiency is a common central pathological factor of a number of diseases and aging: mechanisms and therapeutic implications. Antioxid Redox Signal. https://doi.org/10.1089/ars.2017
Zhang Q, Wei EQ, Zhu CY, Zhang WP, Wang ML, Zhang SH, Yu YP, Chen Z (2006) Focal cerebral ischemia alters the spatio-temporal properties, but not the amount of activity in mice. Behav Brain Res 169(1):66–74
Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D'Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J (2016) NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352(6292):1436–1443
Zhou CC, Yang X, Hua X, Liu J, Fan MB, Li GQ, Song J, Xu TY, Li ZY, Guan YF, Wang P, Miao CY (2016) Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing. Br J Pharmacol 173(15):2352–2368
The authors are grateful to the Core Facilities of Zhejiang University Institute of Neuroscience for technical assistance.
This work was supported by grants from the National Key R&D Program of China (2018YFA0507700), the National Natural Sciences Foundation of China (81573400), the Zhejiang Provincial Natural Science Foundation of China (LY18H170001), and Public Technology Application Research of Zhejiang Province (2016F82G2010036).
Conflict of interests
The authors have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Xie, X., Gao, Y., Zeng, M. et al. Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer’s disease model mice. Metab Brain Dis 34, 353–366 (2019). https://doi.org/10.1007/s11011-018-0346-8
- Nicotinamide adenine dinucleotide (NAD)
- Nicotinamide ribose (NR)
- Alzheimer’s disease (AD)