Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau
Open accessAbstract
Memory loss is the signature feature of Alzheimer's disease, and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD + -dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated α-tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of monoubiquitin-conjugated tau, suggesting that this posttranslationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau in vitro increased clearance and decreased accumulation of tau compared with wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.
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Four months of NAM treatment increased p25 levels 2-fold, reduced p-TauThr231 levels, and improved cognitive function in 3xTgAD mice.
“Four months of NAM treatment increased the level of p25 2-fold, reduced p-TauThr231 levels, and improved cognitive function in 3xTgAD mice (Green et al., 2008).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Green et al., 2008
NAD+ augmentation inhibited Tau phosphorylation at Thr181, Ser202, Thr205, and Thr231, possibly through suppression of cyclin-dependent kinase 5 (Cdk5)-p25 complex activity.
“NAD+ augmentation inhibited Tau phosphorylation at different sites (Thr181, Ser202, Thr205, and Thr231) possibly through suppression of cyclin-dependent kinase 5 (Cdk5)-p25 complex activity (Fang et al., 2019; Green et al., 2008).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Green et al., 2008
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Degradation of Microtubule‐Associated Protein 2 and Brain Spectrin by Calpain: A Comparative Study
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“An impact on microtubule stability would therefore be significant in AD as tau pathology leads to the breakdown of microtubules leading to impairments in neuronal transport (Alonso et al., 1997; Ebneth et al., 1998; Sengupta et al., 1998; Evans et al., 2000).”
BackgroundHistone deacetylase inhibitors open new doors in cancer therapy
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BackgroundInfluentialLearning Decreases Aβ*56 and Tau Pathology and Ameliorates Behavioral Decline in 3xTg-AD Mice
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“Vehicletreated 3xTg-AD mice reached criterion in 6 d, in line with previous findings (Billings et al., 2007), whereas 3xTg-AD mice treated with nicotinamide required only 4 d (Fig.”
ResultSelf-citationSorting of Fas ligand to secretory lysosomes is regulated by mono-ubiquitylation and phosphorylation
Zuccato, E., Blott, E. J., Holt, O. J., Sigismund, S., Shaw, M. K., Bossi, G., & Griffiths, G. M. (2006) · Journal of Cell Science · doi:10.1242/jcs.03315 · Cited by 123 · see citing works
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MAP2c, but Not Tau, Binds and Bundles F-Actin via Its Microtubule Binding Domain
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“MAP2c is 80% homologous to tau within its microtubule binding domains (Roger et al., 2004), and the two proteins display similar microtubule binding affinity.”
BackgroundInfluentialNeuroprotective Effects of Phenylbutyrate Against MPTP Neurotoxicity
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“In addition to the polyglutamine repeat diseases, beneficial effects of HDAC inhibitors have been reported in animal models of Parkinson’s disease (PD), ALS, and experimental autoimmune encephalomyelitis (Gardian et al., 2004; Camelo et al., 2005; Ryu et al., 2005; Fischer et al., 2007).”
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“…complements a number of emerging studies showing that Sir2 inhibitors improve pathology in other neurodegenerative diseases including Huntington’s disease and other models of polyglutamine repeat disorders (Ghosh and Feany, 2004; Pallos et al., 2008) and Parkinson’s disease (Outeiro et al., 2007).”
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“Microtubules are composed of - and -tubulin dimers, and posttranslational modifications such as acetylation and detyrosination increase their stability (Cambray-Deakin and Burgoyne, 1987).”
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“Similarly, p25 expression is associated with improved learning and memory through its role in upregulation of neuronal structural and synaptic proteins (Angelo et al., 2003; Fischer et al., 2005).”
BackgroundResultInfluentialOddo, S., Caccamo, A., Cheng, D., Jouleh, B., Torp, R., & LaFerla, F. M. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04607.x · Cited by 78 · cited 1× · see citing works
“Phosphorylation of tau at Thr231 can occur via either of the major tau kinases, GSK3 or Cdk5, both of which show increasing activity with increasing age in either 3xTg-AD or nonTg mice, but no differences between the two genotypes at 8 months of age (Oddo et al., 2007).”
BackgroundSelf-citationThe cytoskeleton in Alzheimer disease
Terry, R. (1998) · Journal of neural transmission. Supplementum · doi:10.1007/978-3-7091-6467-9_12 · Cited by 70 · cited 2× · see citing works
“These impairments may be involved in the synaptic loss and subsequent retrograde degeneration (Terry, 1998; Mandelkow et al., 2003) characteristic of neurodegeneration in AD.”
BackgroundDemarin, V., Podobnik, S. S., Štorga-Tomić, D., & Kay, G. (2004) · PubMed · Cited by 65 · see citing works
No evidence for cognitive improvement from oral nicotinamide adenine dinucleotide (NADH) in dementia
Rainer, M., Kraxberger, E., Haushofer, M., Mucke, H. A. M., & Jellinger, K. A. (2000) · Journal of Neural Transmission · doi:10.1007/s007020070011 · Cited by 46 · cited 1× · see citing works
“Previous clinical trials with oral NADH have been performed and showed mixed results (Rainer et al., 2000; Demarin et al., 2004).”
ResultAn Alzheimer's disease hypothesis based on transcriptional dysregulation
Robakis, N. K. R. K. (2003) · Amyloid · doi:10.3109/13506120309041729 · Cited by 35 · see citing works
Shinpo (2000) · doi:10.1002/1097-4547(20001101)62:3
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Alzheimer’s disease: Clinical trials and drug development
Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P., & Kivipelto, M. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70119-8 · Cited by 1,217 · see citing works
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
Xie, N., Zhang, L., Gao, W. Q., Huang, C., Huber, P., Zhou, X., Li, C. L., Shen, G., & Zou, B. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00311-7 · Cited by 1,078 · see citing works
“NAD+ accumulation may inhibit the phosphorylation of different Tau protein sites by inhibiting the activity of Cdk5-p25 complex.501 Nicotinamide, as a competitive inhibitor of sirtuins, specifically reduces the phosphorylation of tau (Thr231), which is related to microtubule depolymerization in an analogous manner to…”
ResultInfluentialCalabrese, V., Cornelius, C., Dinkova‐Kostova, A. T., Calabrese, E. J., & Mattson, M. P. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.3074 · Cited by 803 · see citing works
“Others have reported that nicotinamide treatment restores cognitive performance in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and reduction of levels of hyperphosphorylated tau (194).”
NAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790 · see citing works
“Based on the promising data from ADmice (Green et al., 2008), a phase II clinical trial of NAMon 15ADpatients withmild tomoderate dementia (1,500 mg twice daily) for 24 weeks was performed (NCT00580931) (Phelan et al., 2017).”
InfluentialTherapeutic application of histone deacetylase inhibitors for central nervous system disorders
Kazantsev, A. G., & Thompson, L. M. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2681 · Cited by 715 · see citing works
Self-citationMultiple roles of HDAC inhibition in neurodegenerative conditions
Chuang, D.-M., Leng, Y., Marinova, Z., Kim, H.-J., & Chiu, C.-T. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.06.002 · Cited by 676 · see citing works
“Nicotinamide, also known as niacinamide, is a precursor of NAD+ and a competitive Class III HDAC inhibitor that can be given orally [20].”
BackgroundKapogiannis, D., & Mattson, M. P. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70277-5 · Cited by 594 · see citing works
Dagher, N. N., Najafi, A. R., Kayala, K. M. N., Elmore, M. R. P., White, T. E., Medeiros, R., West, B. L., & Green, K. N. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0366-9 · Cited by 505 · see citing works
“Aβ ELISA Aß1–40 and Aß1–42 were measured using a sensitive sandwich ELISA system as previously described [16].”
MethodSelf-citationEpigenetic mechanisms in neurological disease
Jakovcevski, M., & Akbarian, S. (2012) · Nature Medicine · doi:10.1038/nm.2828 · Cited by 450 · see citing works
Perez Ortiz, J. M., & Swerdlow, R. H. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14585 · Cited by 426 · see citing works
Mitochondrial dysfunction in neurodegenerative disorders
Klemmensen, M. M., Borrowman, S. H., Pearce, C., Pyles, B., & Chandra, B. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2023.10.002 · Cited by 396 · see citing works
“The proposed method of action for nicotinamide is through the conversion of nicotinamide to NAD þ , inhibiting sirtuin and reducing levels of Thr231-Phosphotau [143].”
MethodRole of NAD+ in regulating cellular and metabolic signaling pathways
Amjad, S., Nisar, S., Bhat, A. A., Shah, A. R., Frenneaux, M. P., Fakhro, K. A., Haris, M., Reddy, R. D., Patay, Z. J., Baur, J. A., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101195 · Cited by 394 · see citing works
“Several studies have reported a decline in levels of NMNAT2 before neurodegeneration in mouse models of dementia, Parkinsonism-17, and AD [101,102].”
BackgroundThe epigenetics of aging and neurodegeneration
Lardenoije, R., Iatrou, A., Kenis, G., Kompotis, K., Steinbusch, H. W. M., Mastroeni, D., Coleman, P., Lemere, C. A., Hof, P. R., van den Hove, D. L. A., et al. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.002 · Cited by 381 · see citing works
“with nicotinamide was observed to restore cognitive impairments in 3xTg-AD mice, by indirectly promoting microtubule stability, which is affected by hyperphosphorylated tau in AD (Green et al., 2008).”
BackgroundAlzheimer's Disease and the Amyloid Cascade Hypothesis: A Critical Review
Reitz, C. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/369808 · Cited by 373 · see citing works
“Furthermore, nicotinamide inhibits brain sirtuin deacetylase and upregulates acetyl-αtubulin, protein p25, and MAP2c; all these interactions are associated with increased microtubule stabilization [100].”
BackgroundRicobaraza, A., Cuadrado-Tejedor, M., Pérez-Mediavilla, A., Frechilla, D., Del Río, J., & García-Osta, A. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2008.229 · Cited by 423 · see citing works
“This is consonant with recent observations suggesting the beneficial effects of reducing tau to prevent behavioral deficits in AD transgenic mice without altering their high Ab levels (Roberson et al, 2007; Green et al, 2008).”
BackgroundResultAutophagy in Alzheimer’s disease pathogenesis: Therapeutic potential and future perspectives
Zhang, Z., Yang, X., Song, Y., & Tu, J. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101464 · Cited by 378 · see citing works
Phosphorylation of different tau sites during progression of Alzheimer’s disease
Neddens, J., Temmel, M., Flunkert, S., Kerschbaumer, B., Hoeller, C., Loeffler, T., Niederkofler, V., Daum, G., Attems, J., & Hutter-Paier, B. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0557-6 · Cited by 384 · see citing works
“In the diseased brain, ptau sites are commonly associated with tau aggregation processes such as incomplete binding and destabilization of microtubules, causing the transition from pre-tangles to NFT formation [12, 16, 21, 28, 32].”
BackgroundGong, B., Pan, Y., Vempati, P., Zhao, W., Knable, L., Ho, L., Wang, J., Sastre, M., Ono, K., Sauve, A. A., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.005 · Cited by 345 · see citing works
“The other hemispherewas fixed in formaldehyde for subsequent stereological quantitative assessments of neuritic plaque pathology, as previously described (Green et al., 2008; Wang et al., 2008).”
The emerging field of epigenetics in neurodegeneration and neuroprotection
Hwang, J.-Y., Aromolaran, K. A., & Zukin, R. S. (2017) · Nature reviews. Neuroscience · doi:10.1038/nrn.2017.46 · Cited by 343 · see citing works
Janke, C., & Kneussel, M. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.05.001 · Cited by 335 · see citing works
Shukla, S., & Tekwani, B. L. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00537 · Cited by 314 · see citing works
Dysregulation of Histone Acetylation in the APP/PS1 Mouse Model of Alzheimer's Disease
Francis, Y. I., Fà, M., Ashraf, H., Zhang, H., Staniszewski, A., Latchman, D. S., & Arancio, O. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1134 · Cited by 296 · see citing works
“In fact, Green and colleagues [33] showed that inhibition of class III NAD + - dependent HDACs using vitamin B3 restored cognitive deficits in the triple transgenic AD mice, via a mechanism involving the reduction of Thr231-phosphotau.”
The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences
Cyr, A. R., & Domann, F. E. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3492 · Cited by 294 · see citing works
SIRT2: Controversy and multiple roles in disease and physiology
Wang, Y., Yang, J., Hong, T., Chen, X., & Cui, L. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100961 · Cited by 289 · see citing works
Epigenetic regulation in the pathophysiology of Alzheimer's disease
Chouliaras, L., Rutten, B. P. F., Kenis, G., Peerbooms, O., Visser, P. J., Verhey, F., van Os, J., Steinbusch, H. W. M., & van den Hove, D. L. A. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.01.002 · Cited by 262 · see citing works
Liu, D., Gharavi, R. B., PITTA, M. G. R., Gleichmann, M., & Mattson, M. P. (2009) · NeuroMolecular Medicine · doi:10.1007/s12017-009-8058-1 · Cited by 248 · see citing works
“The deaths of many neurons that occur following a stroke involves, in part, excitotoxicity which can manifest as necrosis or apoptosis (Beal 1992; Greene and Greenamyre 1996; Ankarcrona et al. 1995).”
BackgroundGenetic mouse models of brain ageing and Alzheimer's disease
Bilkei‐Gorzó, A. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.12.009 · Cited by 244 · see citing works
Liu, D., Pitta, M., Jiang, H., Lee, J.-H., Zhang, G., Chen, X., Kawamoto, E. M., & Mattson, M. P. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.020 · Cited by 238 · see citing works
“Other studies have suggested that Class III HDAC inhibitors can suppress the activity of multiple HDACs in addition to SIRT1, and account for their neuroprotective effects (Green et al., 2008; Langley et al., 2005; Roth et al., 2001).”
InfluentialHannan, A. J. (2014) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12102 · Cited by 240 · see citing works
Epigenetic targeting of histone deacetylase: Therapeutic potential in Parkinson's disease?
Harrison, I. F., & Dexter, D. T. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.05.010 · Cited by 227 · see citing works
“, 1999), restore cognitive function in transgenicmodels of AD (Green et al., 2008), and improvemotor deficits”
BackgroundSirtuin deacetylases in neurodegenerative diseases of aging
Herskovits, A. Z., & Guarente, L. (2013) · Cell Research · doi:10.1038/cr.2013.70 · Cited by 222 · see citing works
Kumar, V., Kundu, S., Singh, A., & Singh, S. (2022) · Current Neuropharmacology · doi:10.2174/1570159x19666210609160017 · Cited by 210 · see citing works
Targeting HDACs: A Promising Therapy for Alzheimer's Disease
Xu, K., Dai, X., Huang, H., & Jiang, Z.-F. (2011) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2011/143269 · Cited by 206 · see citing works
“Nicotinamide, as the precursor of NAD+, inhibits class III HDAC proteins [14].”
BackgroundInfluentialThe Influence of Nicotinamide on Health and Disease in the Central Nervous System
Fricker, R. A., Green, E. L., Jenkins, S. I., & Griffin, S. M. (2018) · International Journal of Tryptophan Research · doi:10.1177/1178646918776658 · Cited by 200 · see citing works
Long, A. N., Owens, K., Schlappal, A. E., Kristián, T., Fishman, P. S., & Schuh, R. A. (2015) · BMC Neurology · doi:10.1186/s12883-015-0272-x · Cited by 198 · see citing works
“[41] treated four months old triple transgenic AD mice for 4 months, finding NAM treatment decreased tau levels and improved cognition.”
BackgroundSIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases
Manjula, R., Anuja, K., & Alcain, F. J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.585821 · Cited by 193 · see citing works
Chow, S. F., Chen, M., Shi, L., Chow, A. H. L., & Sun, C. C. (2012) · Pharmaceutical Research · doi:10.1007/s11095-012-0709-5 · Cited by 193 · see citing works
“Apart from being readily water-soluble and chemically compatible with either profen, NCT has demonstrated an ability to restore cognition in AD transgenic mice through sirtuin inhibition and selective reduction of Thr231-Phosphotau (18).”
BackgroundRegulation of neuron mitochondrial biogenesis and relevance to brain health
Onyango, I. G., Lu, J., Rodova, M., Lezi, E., Crafter, A. B., & Swerdlow, R. H. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.07.014 · Cited by 188 · see citing works
“E D However, since HDAC inhibitors, including nicotinamide, confer neuroprotective effects in models of neurodegenerative diseases [120, 121], the role of HDAC in neuronal survival becomes complicated.”
BackgroundSaini, J. S., Corneo, B., Miller, J. D., Kiehl, T. R., Wang, Q., Boles, N. C., Blenkinsop, T. A., Stern, J. H., & Temple, S. (2017) · Cell stem cell · doi:10.1016/j.stem.2016.12.015 · Cited by 187 · see citing works
“, 2009), can restore cognition in AD mice (Green et al., 2008) and is in clinical trial for AD (NCT00580931).”
BackgroundSIRT1 in the brain—connections with aging-associated disorders and lifespan
Ng, F. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00064 · Cited by 185 · see citing works
“However, contrasting the above, the SIRT1 inhibitor nicotinamide was also shown to attenuate/delay cognitive effects of 3xTg-AD mice (triple transgenic for mutant Psen1, App(swe) and Tau) via SIRT1 inhibition and reduction of Tau phosphorylation (Green et al., 2008).”
Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells
Hwang, E. S., & Song, S. B. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2527-8 · Cited by 178 · see citing works
Valor, L. M., Viosca, J., López‐Atalaya, J. P., & Barco, Á. (2013) · Current Pharmaceutical Design · doi:10.2174/13816128113199990382 · Cited by 168 · see citing works
“Furthermore, HDACi administration recovers memory-related functions and enhances LTP in AD models [150, 151, 170-174].”
BackgroundPhosphorylation of Threonine 3
Aiken, C. T., Steffan, J. S., Guerrero, C., Khashwji, H., Lukácsovich, T., Simmons, D. A., Purcell, J., Menhaji, K., Zhu, Y., Green, K., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.013193 · Cited by 172 · see citing works
Self-citationTurunc Bayrakdar, E., Uyanikgil, Y., Kanit, L., Koylu, E., & Yalcin, A. (2014) · Free Radical Research · doi:10.3109/10715762.2013.857018 · Cited by 169 · see citing works
“with microtubule depolymerization [65].”
Calorie restriction mimetics: Can you have your cake and eat it, too?
Ingram, D. K., & Roth, G. S. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.11.005 · Cited by 162 · see citing works
Guo, W., Qian, L., Zhang, J., Zhang, W., Morrison, A., Hayes, P. D., Wilson, S., Chen, T., & Zhao, J. (2011) · Journal of Neuroscience Research · doi:10.1002/jnr.22725 · Cited by 162 · see citing works
“Journal of Neuroscience Research understanding of the reciprocal relationship between Sirt1 and mTOR in the CNS by observing concomitant overexpression of Sirt1 and down-regulation of mTOR signaling as well as up-regulation of mTOR signaling occurring with Sirt1 knockdown in neurons.”
BackgroundInfluentialSirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease
Zhou, X., Fan, L. X., Sweeney, W. E., Denu, J. M., Avner, E. D., & Li, X. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64401 · Cited by 160 · see citing works
GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia
Xu, M., & Wong, A. H. C. (2018) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.172 · Cited by 159 · see citing works
Epigenetics in Alzheimer’s Disease: Perspective of DNA Methylation
Qazi, T. J., Quan, Z., Mir, A., & Qing, H. (2018) · Molecular Neurobiology · doi:10.1007/s12035-016-0357-6 · Cited by 153 · see citing works
Smith, M. R., Syed, A., Lukácsovich, T., Purcell, J., Barbaro, B. A., Worthge, S. A., Wei, S. R., Pollio, G., Magnoni, L., Scali, C., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu010 · Cited by 151 · see citing works
“Our study and others support the notion that inhibition of Sir2 is protective in various neurodegenerative environments such as AD mice (12), Ataxin-3-challenged Drosophila (11), oxidatively damaged cells (10), Drosophila models of HD (9) and mHtt-challenged Drosophila, mammalian cells and mice challenged with mHtt ex…”
BackgroundSIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy
Min, S., Sohn, P., Li, Y., Devidze, N., Johnson, J. R., Krogan, N. J., Masliah, E., Mok, S., Gestwicki, J. E., & Gan, L. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2369-17.2018 · Cited by 148 · see citing works
“However, inhibition of SIRT1 alleviates pathology and restores cognition in pathological mouse models of Huntington’s disease (Smith et al., 2014) and AD (Green et al., 2008), respectively.”
BackgroundPossible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment
Hwang, E., & Song, S. (2020) · Biomolecules · doi:10.3390/biom10050687 · Cited by 144 · see citing works
“Decreased AD pathology and cognitive decline [10]”
BackgroundThe Epigenetics of Alzheimer’s Disease: Factors and Therapeutic Implications
Liu, X., Jiao, B., & Shen, L. H. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00579 · Cited by 147 · see citing works
Sung, Y. M., Lee, T., Yoon, H., DiBattista, A. M., Song, J. M., Sohn, Y., Moffat, E. I., Turner, R. S., Jung, M., Kim, J., et al. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2012.10.005 · Cited by 137 · see citing works
“Interestingly, the HDACI nicotinamide increases the level of acetylated α-tubulin, and selectively decreases Thr231-phosphotau in 3xTg AD mice (Green et al., 2008; Hempen and Brion, 1996).”
HDAC6 α-tubulin deacetylase: A potential therapeutic target in neurodegenerative diseases
Li, G., Jiang, H., Chang, M., Xie, H., & Hu, L. (2011) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2011.02.017 · Cited by 137 · see citing works
Epigenetic mechanisms in Alzheimer's disease: Implications for pathogenesis and therapy
Wang, J., Yu, J., Tan, M., Jiang, T., & Tan, L. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2013.05.003 · Cited by 135 · see citing works
Konsoula, Z., & Barile, F. A. (2012) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/j.vascn.2012.08.001 · Cited by 134 · see citing works
Kelly, G. S. (2010) · PubMed · Cited by 135 · see citing works
Cognitive Decline in Preclinical Alzheimer’s Disease: Amyloid-Beta versus Tauopathy
Huber, C. M., Yee, C., May, T., Dhanala, A., & Mitchell, C. S. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170490 · Cited by 131 · see citing works
Tauopathy: A common mechanism for neurodegeneration and brain aging
Saha, P., & Sen, N. (2019) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2019.01.007 · Cited by 128 · see citing works
Liver X receptor activation restores memory in aged AD mice without reducing amyloid
Vanmierlo, T., Rutten, K., Dederen, J., Bloks, V. W., van Vark-van der Zee, L. C., Kuipers, F., Kiliaan, A., Blokland, A., Sijbrands, E. J. G., Steinbusch, H., et al. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.07.005 · Cited by 154 · see citing works
Design, Synthesis, and Biological Activity of a Novel Series of Human Sirtuin-2-Selective Inhibitors
Suzuki, T., Khan, M. N. A., Sawada, H., Imai, E., Itoh, Y., Yamatsuta, K., Tokuda, N., Takeuchi, J., Seko, T., Nakagawa, H., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3002108 · Cited by 128 · see citing works
Gu, X., Sun, J., Li, S., Wu, X., & Li, L. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.10.013 · Cited by 127 · see citing works
“Moreover, some other studies have demonstrated that the memory deficits can be partially recovered by histone deacetylase (HDAC) inhibitor in an AD transgenic mice model (Fischer et al., 2007; Green et al., 2008; Ricobaraza et al., 2009).”
BackgroundHathorn, T., Snyder-Keller, A., & Messer, A. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.08.017 · Cited by 123 · see citing works
HDAC inhibitors and neurodegeneration: At the edge between protection and damage
Dietz, K. C., & Casaccia, P. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.01.011 · Cited by 126 · see citing works
“Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, et al. Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau.”
BackgroundInfluentialWhiley, L., Chappell, K. E., D’Hondt, E., Lewis, M. R., Jiménez, B., Snowden, S. G., Soininen, H. S., Kłoszewska, I., Mecocci, P., Tsolaki, M., et al. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00741-z · Cited by 123 · see citing works
Ghosh, D., LeVault, K. R., Barnett, A., & Brewer, G. J. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6192-11.2012 · Cited by 121 · see citing works
“Reversal of NAD(P)H and redox deficits with nicotinamide Nicotinamide, a precursor of NAD (Ying, 2008), reverses learning deficits in the 3xTg-AD mouse (Green et al., 2008) with a mechanism attributed to epigenetic changes based on acetylation of phospho-tau Thr231.”
BackgroundInfluentialCorpas, R., Revilla, S., Ursulet, S., Castro, M., Kaliman, P., Petegnief, V., Giménez‐Llort, L., Sarkis, C., Pallàs, M., & Sanfeliu, C. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0087-9 · Cited by 121 · see citing works
“Moreover, the sirtuin inhibitor nicotinamide has been reported to decrease tau pathology in 3xTg-AD mice through selective reduction of a specific p-tau species and increase of microtubule stability [66], showing the involvement of alternative neuroprotective pathways.”
Albani, D., Polito, L., & Forloni, G. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1215 · Cited by 122 · see citing works
Pharmacological Treatment of Alzheimer Disease
Massoud, F., & Léger, G. C. (2011) · The Canadian Journal of Psychiatry · doi:10.1177/070674371105601003 · Cited by 122 · see citing works
The Current State of NAD+‐Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets
Schiedel, M., Robaa, D., Rumpf, T., Sippl, W., & Jung, M. (2017) · Medicinal Research Reviews · doi:10.1002/med.21436 · Cited by 122 · see citing works
Current therapeutic targets for the treatment of Alzheimer’s disease
Grill, J. D., & Cummings, J. L. (2010) · Expert Review of Neurotherapeutics · doi:10.1586/ern.10.29 · Cited by 121 · see citing works
SIRT1 gene is associated with major depressive disorder in the Japanese population
Kishi, T., Yoshimura, R., Kitajima, T., Okochi, T., Okumura, T., Tsunoka, T., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., Fukuo, Y., et al. (2010) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.04.003 · Cited by 136 · see citing works
“reported that nicotinamide, a well-known inhibitor of SIRT1 used for in vivo studies (Green et al., 2008; Liu et al., 2009), brought mice similar phenotypes (small size, weight loss and decreased motor activity) to dopamine-deficient ones and SIRT1 gene knockout ones (Lee et al.”
BackgroundTuning acetylation levels with HAT activators: Therapeutic strategy in neurodegenerative diseases
Selvi, B. R., Cassel, J., Kundu, T. K., & Boutillier, A. (2010) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2010.08.012 · Cited by 117 · see citing works
“Interestingly, the competitive inhibitor of the sirtuins, belonging to the class III NAD-dependent HDACs, was tested in the triple transgenic AD model: 3xTg-AD mice [163].”
BackgroundEpigenetics: A novel therapeutic approach for the treatment of Alzheimer's disease
Adwan, L. I., & Zawia, N. H. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.03.010 · Cited by 114 · see citing works
“Interestingly, the nonselective SIRT inhibitor nicotinamide lowers phosphorylated tau and improves cognition in micedemonstrating that SIRTmodulation involves complexmechanisms (Green et al., 2008; Stunkel & Campbell, 2011).”
Alzheimer’s Disorder: Epigenetic Connection and Associated Risk Factors
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“2 Nicotinamide/niacinamide Nicotinamide (Table 4), a competitive inhibitor of class III NAD-dependent HDACs, selectively reduces specific phospho-species of tau (Thr231) associated with microtubule depolymerization, increases acetylated a-tubulin, a primary substrate of SIRT2, and MAP2c, linked to increased microtubul…”
Background
- Authors
- Green, K. N., Steffan, J. S., Martinez-Coria, H., Sun, X., Schreiber, S. S., Thompson, L. M., & LaFerla, F. M.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- LaFerla, Frank M.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-11-05
- Volume
- 28
- Issue
- 45
- Pages
- 11500-11510
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2617713
- OpenAlex
- W2089740883
- Cited by
- 404
- References
- 59
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 25 · 2023: 24 · 2022: 18 · 2021: 23 · 2020: 23 · 2019: 21 · 2018: 21 · 2017: 28 · 2016: 18 · 2015: 18 · 2014: 29 · 2013: 27 · 2012: 28
- FWCI
- 16.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- Alzheimer's Drug Discovery Foundation
- National Institutes of Health
- National Institute on Aging (AG0212982, R01AG021982)
- National Institute of Neurological Disorders and Stroke (R01NS052789, NS52789)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- nicotinamide, Alzheimer's disease, sirtuins, SIRT1, SIRT2, tau phosphorylation, acetylated alpha-tubulin, microtubule stability, histone deacetylase inhibition, 3xTg-AD mice, cognitive impairment, tau clearance, tauopathy, memory loss
- MeSH terms
- Alzheimer Disease, Animals, Behavior, Animal, Butyrates, Cell Line, Transformed, Cognition Disorders, Disease Models, Animal, Enzyme Inhibitors, Humans, Mice, Inbred C57BL, Mice, Transgenic, Microtubule-Associated Proteins, Mutation, Niacinamide, Peptide Fragments, Phosphorylation, Threonine, Time Factors, Transfection, Tubulin, Vitamin B Complex, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Maze Learning, Sirtuins, Immunoprecipitation, Mice, Presenilin-1
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