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Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession
Open accessAbstract
Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathologic accumulations of amyloid β-peptide (Aβ) and hyperphosphorylated tau in Alzheimer's disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the β-nicotinamide adenine dinucleotide precursor nicotinamide on brain cell mitochondrial function and macroautophagy, bioenergetics-related signaling, and cognitive performance were studied in cultured neurons and in a mouse model of AD. Oxidative stress resulted in decreased mitochondrial mass, mitochondrial degeneration, and autophagosome accumulation in neurons. Nicotinamide preserved mitochondrial integrity and autophagy function, and reduced neuronal vulnerability to oxidative/metabolic insults and Aβ toxicity. β-Nicotinamide adenine dinucleotide biosynthesis, autophagy, and phosphatidylinositol-3-kinase signaling were required for the neuroprotective action of nicotinamide. Treatment of 3xTgAD mice with nicotinamide for 8 months resulted in improved cognitive performance, and reduced Aβ and hyperphosphorylated tau pathologies in hippocampus and cerebral cortex. Nicotinamide treatment preserved mitochondrial integrity, and improved autophagy-lysosome procession by enhancing lysosome/autolysosome acidification to reduce autophagosome accumulation. Treatment of 3xTgAD mice with nicotinamide resulted in elevated levels of activated neuroplasticity-related kinases (protein kinase B [Akt] and extracellular signal-regulated kinases) and the transcription factor cyclic adenosine monophosphate (AMP) response element-binding protein in the hippocampus and cerebral cortex. Thus, nicotinamide suppresses AD pathology and cognitive decline in a mouse model of AD by a mechanism involving improved brain bioenergetics with preserved functionality of mitochondria and the autophagy system.
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“In different neurodegenerative mouse models including AD, HD, and the premature aging disease A-T, NAD+ augmentation increases the expression and activity of BDNF, leading to enhanced synaptic plasticity and function (Fang et al., 2016a; Hathorn et al., 2011; Liu et al., 2013).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Liu et al., 2013
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“Exposure of cultured rat cortical neurons to aggregating Aβ results in reduced NAD+ levels (Liu et al., 2013).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Liu et al., 2013
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“Accordingly, NAD+ augmentation inhibited AD-related pathology and cognitive decline in different AD animal models, including 3xTgAD mice treated with NAM (Liu et al., 2013), 3xTgAD/Polβ+/− mice treated with NR (Hou et al., 2018), and in neuronal Aβ1–42 and the neuronal Tau (pro-aggregant F3ΔK280 tau fragment) transgenic C. elegans models (Fang et al., 2019) (summarized in Table 1).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Liu et al., 2013
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Metadata
- Authors
- Liu, D., Pitta, M., Jiang, H., Lee, J.-H., Zhang, G., Chen, X., Kawamoto, E. M., & Mattson, M. P.
- Affiliations
- National Institute on Aging (US)
- Konkuk University (KR)
- National Institutes of Health (US)
- Corresponding author
- Mattson, Mark P.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 34
- Issue
- 6
- Pages
- 1564-1580
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3596471
- OpenAlex
- W1996656477
- Cited by
- 238
- References
- 101
- Citations by year
- 2026: 11 · 2025: 29 · 2024: 23 · 2023: 19 · 2022: 21 · 2021: 37 · 2020: 16 · 2019: 17 · 2018: 17 · 2017: 13 · 2016: 10 · 2015: 10 · 2014: 8 · 2013: 7
- FWCI
- 5.36
- 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
- Intramural Research Program of the National Institute on Aging
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- nicotinamide, Alzheimer's disease, brain energy metabolism, mitochondrial function, autophagy, oxidative stress, amyloid-beta, hyperphosphorylated tau, 3xTg-AD mice, cognitive decline, phosphatidylinositol 3-kinase signaling, AMPK, lysosomal acidification, neuroprotection, hippocampus
- MeSH terms
- Alzheimer Disease, Animals, Autophagy, Cells, Cultured, Cognition Disorders, Disease Models, Animal, Energy Metabolism, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Niacinamide, Vitamin B Complex, Oxidative Stress, Mice, Rats
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