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
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Nicotinamide adenine dinucleotide (NAD)(+), a coenzyme involved in redox activities in the mitochondrial electron transport chain, has been identified as a key regulator of the lifespan-extending effects, and the activation of NAD(+) expression has been linked with a decrease in beta-amyloid (Aβ) toxicity in Alzheimer's disease (AD). Nicotinamide riboside (NR) is a NAD(+) precursor, it promotes peroxisome proliferator-activated receptor-γ coactivator 1 (PGC)-1α expression in the brain. Evidence has shown that PGC-1α is a crucial regulator of Aβ generation because it affects β-secretase (BACE1) degradation. In this study we tested the hypothesis that NR treatment in an AD mouse model could attenuate Aβ toxicity through the activation of PGC-1α-mediated BACE1 degradation. Using the Tg2576 AD mouse model, using in vivo behavioral analyses, biochemistry assays, small hairpin RNA (shRNA) gene silencing and electrophysiological recording, we found (1) dietary treatment of Tg2576 mice with 250 mg/kg/day of NR for 3 months significantly attenuates cognitive deterioration in Tg2576 mice and coincides with an increase in the steady-state levels of NAD(+) in the cerebral cortex; (2) application of NR to hippocampal slices (10 μM) for 4 hours abolishes the deficits in long-term potentiation recorded in the CA1 region of Tg2576 mice; (3) NR treatment promotes PGC-1α expression in the brain coinciding with enhanced degradation of BACE1 and the reduction of Aβ production in Tg2576 mice. Further in vitro studies confirmed that BACE1 protein content is decreased by NR treatment in primary neuronal cultures derived from Tg2576 embryos, in which BACE1 degradation was prevented by PGC-1α-shRNA gene silencing; and (4) NR treatment and PGC-1α overexpression enhance BACE1 ubiquitination and proteasomal degradation. Our 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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NR protects cognitive function, synaptic plasticity, learning, memory, and motor function in Alzheimer disease models.
“NR demonstrated protective effects on cognitive function, synaptic plasticity, learning, memory, and motor function in Alzheimer’s disease models [24, 27].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [27]
Results §3.1 reports improved object-recognition performance in NR-treated Tg2576 Alzheimer’s-model mice, supporting the cognitive, learning and memory aspects. Results §3.3 reports improved hippocampal long-term potentiation, supporting synaptic plasticity. The paper does not report a motor-function outcome, so it does not support that part of the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measuredNR reduced beta-amyloid levels and increased the chance of recognizing a novel object by 20% in NR-treated Tg2576 mice.
“It reduced the beta-amyloid levels, increasing the chance of recognizing a novel object by 20% in NR-treated Tg2576 mice [27].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [27]
NAD+ augmentation via nicotinamide riboside supplementation induced the ubiquitin-proteasome system in both the hippocampus and cortex of Tg2576 Alzheimer's disease mice and restored the mitochondrial unfolded protein response in APPswe/PSEN1dE9 AD mice.
“NAD+ augmentation via NR supplementation induced UPS in both the hippocampus and cortex of Tg2576 AD mice (Gong et al., 2013) and restored UPRmt in APPswe/PSEN1dE9 AD mice.”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Gong et al., 2013
NAD+ depletion is reported in several models of accelerated ageing that exhibit neurodegeneration, as well as in neurodegenerative diseases including Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis.
“NAD+ depletion is reported in several models of accelerated ageing which exhibit neurodegeneration33,134,135, as well as in neuro-degenerative diseases, including Alzheimer disease136, Parkinson disease137,138 and amyotrophic lateral sclerosis (ALS)139.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [136]
NAD+ precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease, and show neuroprotective properties in Drosophila models of Parkinson disease and mouse models of ALS.
“the NAD+ precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease136,161,175–180, and also showed neuroprotective properties in Drosophila melanogaster models of Parkinson disease181,182 and in mouse models of ALS139.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [136]
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- Authors
- Gong, B., Pan, Y., Vempati, P., Zhao, W., Knable, L., Ho, L., Wang, J., Sastre, M., Ono, K., Sauve, A. A., & Pasinetti, G. M.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Imperial College London (GB)
- Weill Cornell Medicine (US)
- James J. Peters VA Medical Center (US)
- Corresponding author
- Pasinetti, Giulio M.
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 34
- Issue
- 6
- Pages
- 1581-1588
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3632303
- OpenAlex
- W2166956025
- Cited by
- 345
- References
- 34
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 28 · 2023: 36 · 2022: 33 · 2021: 40 · 2020: 32 · 2019: 32 · 2018: 27 · 2017: 27 · 2016: 18 · 2015: 13 · 2014: 11 · 2013: 6
- FWCI
- 11.11
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Veterans Administration by the US National Institutes of Health
- Alzheimer's Association (IIRG-08-89354)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- nicotinamide riboside, Alzheimer's disease, PGC-1α, amyloid-beta, NAD+, Tg2576 mice, cognitive impairment, long-term potentiation, synaptic plasticity, ubiquitination, proteasomal degradation, mitochondrial gene expression, hippocampus
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Alzheimer Disease, Animals, Cells, Cultured, Cognition Disorders, Disease Models, Animal, Gene Expression Regulation, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Niacinamide, Organ Culture Techniques, Pyridinium Compounds, Transcription Factors, Up-Regulation, Aspartic Acid Endopeptidases, Mice, Amyloid Precursor Protein Secretases
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