The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
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
In the citing paper
“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RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769
RetractedAmyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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Resveratrol improves health and survival of mice on a high-calorie diet
Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., et al. (2006) · Nature · doi:10.1038/nature05354 · Cited by 4,290 · cited 1×
“The sirtuin family of deacetylases is implicated in cellular pathways that influence longevity in yeast, C. elegans, Drosophila, and mammals (Tissenbaum and Guarente, 2001; Anderson et al., 2003; Howitz et al., 2003; Wood et al., 2004; Baur et al., 2006).”
BackgroundTriple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126 · cited 6×
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BackgroundMethodInfluentialSelf-citationSmall molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L.-L., et al. (2003) · Nature · doi:10.1038/nature01960 · Cited by 3,796
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“Kim N. Green,1 Joan S. Steffan,2 Hilda Martinez-Coria,1 Xuemin Sun,3 Steven S. Schreiber,3,5 Leslie Michels Thompson,1,2,4 and Frank M. LaFerla1”
BackgroundDent, S., Denu, J. M., & Allis, C. D. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.81 · Cited by 1,906 · cited 2×
“Acetylation of histones and nonhistone transcription factors plays an important role in regulating chromatin condensation and gene transcription (Roth et al., 2001).”
BackgroundReducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007) · Science · doi:10.1126/science.1141736 · Cited by 1,892
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“The sirtuin family of deacetylases is implicated in cellular pathways that influence longevity in yeast, C. elegans, Drosophila, and mammals (Tissenbaum and Guarente, 2001; Anderson et al., 2003; Howitz et al., 2003; Wood et al., 2004; Baur et al., 2006).”
BackgroundIncreased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans
Tissenbaum, H. A., & Guarente, L. (2001) · Nature · doi:10.1038/35065638 · Cited by 1,603 · cited 1×
“The sirtuin family of deacetylases is implicated in cellular pathways that influence longevity in yeast, C. elegans, Drosophila, and mammals (Tissenbaum and Guarente, 2001; Anderson et al., 2003; Howitz et al., 2003; Wood et al., 2004; Baur et al., 2006).”
Background
Research works printed but not linked: 1
- 10.1016/j.neuron.2005.01.040 · DOI · Paper page
Cited by
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Items 401–410 of 410
Păduraru, A. F., Zaharia, R.-S., Roată, I., Hriţcu, L., Boiangiu, R. Ş., Lupașcu, A.-M., Brezuleanu, M. M., & Brezuleanu, C. O. (2026) · Neurology International · doi:10.3390/neurolint18100189
“In Alzheimer’s disease, nicotinamide restored cognitive deficits in 3xTg mice and selectively reduced Thr231-phosphorylated tau; these effects involved sirtuin inhibition, especially inhibition of SIRT2-like tubulin deacetylase activity [126].”
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Echeverría, D. A., Arroyo-Romero, S., Garcia, D. R., Navarro-Matías, E., Navarro-Cáceres, A., Suárez-Moreno, N., Domínguez-Martín, A., Gómez-Marcos, M. Á., Gómez‐Sánchez, M., Gómez‐Sánchez, L., et al. (2026) · Nutrients · doi:10.3390/nu18203370
Epigenetic mechanisms in brain aging and their role in cognitive decline and mental health disorders
Chinn, C., & Wood, M. (2026) · Handbook of clinical neurology · doi:10.1016/b978-0-443-19043-8.00023-2
BindingDB (2012) · UC San Diego · doi:10.7270/q2251jj4
BindingDB Entry 50047462: 5-((3-Amidobenzyl)oxy)nicotinamides as Sirtuin 2 Inhibitors.
BindingDB (2017) · UC San Diego · doi:10.7270/q2z89f9w
Dietary and Metabolic Compounds Affecting Chromatin Dynamics/Remodeling
Milagro, F. I., Campión, J., & Martínez, J. A. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-375709-8.00018-6
Estudo in silico de inibidores de SIRT1
Heberlé, G. (2011) · Americanae (AECID Library)
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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