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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 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
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“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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1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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Background
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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
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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 814
“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
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InfluentialTherapeutic application of histone deacetylase inhibitors for central nervous system disorders
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“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
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“Furthermore, nicotinamide inhibits brain sirtuin deacetylase and upregulates acetyl-αtubulin, protein p25, and MAP2c; all these interactions are associated with increased microtubule stabilization [100].”
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“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.”
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“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).”
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“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).”
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“Nicotinamide, as the precursor of NAD+, inhibits class III HDAC proteins [14].”
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BackgroundSIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases
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BackgroundRegulation of neuron mitochondrial biogenesis and relevance to brain health
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“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
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“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
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“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).”
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Background
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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