A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease
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Alzheimer's disease (AD) involves progressive accumulation of amyloid β-peptide (Aβ) and neurofibrillary pathologies, and glucose hypometabolism in brain regions critical for memory. The 3xTgAD mouse model was used to test the hypothesis that a ketone ester-based diet can ameliorate AD pathogenesis. Beginning at a presymptomatic age, 2 groups of male 3xTgAD mice were fed a diet containing a physiological enantiomeric precursor of ketone bodies (KET) or an isocaloric carbohydrate diet. The results of behavioral tests performed at 4 and 7 months after diet initiation revealed that KET-fed mice exhibited significantly less anxiety in 2 different tests. 3xTgAD mice on the KET diet also exhibited significant, albeit relatively subtle, improvements in performance on learning and memory tests. Immunohistochemical analyses revealed that KET-fed mice exhibited decreased Aβ deposition in the subiculum, CA1 and CA3 regions of the hippocampus, and the amygdala. KET-fed mice exhibited reduced levels of hyperphosphorylated tau deposition in the same regions of the hippocampus, amygdala, and cortex. Thus, a novel ketone ester can ameliorate proteopathic and behavioral deficits in a mouse AD model.
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The ketone β-hydroxybutyrate raises NAD+ in neurons and suppresses Aβ and p-Tau pathologies and ameliorates behavioral deficits in a mouse model of AD.
“the ketone β-hydroxybutyrate, which elevates NAD+ levels in neurons and has been shown to suppress Aβ and p-Tau pathologies and ameliorate behavioral deficits in a mouse model of AD”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Kashiwaya et al., 2013
Several clinical studies have shown a positive effect of a ketogenic diet on patients with AD or mild cognitive impairment (MCI), consistent with preclinical results.
“Several clinical studies have shown a positive effect of a ketogenic diet on patients with AD or mild cognitive impairment (MCI), consistent with preclinical results [87–91] (Table 1).”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [90]
A ketone ester diet, which seemingly recapitulates fasting energy metabolism, alleviates proteopathic and behavioral deficiencies in a mouse model of Alzheimer's disease.
“Interestingly, a ketone ester diet, which seemingly recapitulates fasting energy metabolism, alleviates proteopathic and behavioral deficiencies in a mouse model of Alzheimer’s disease (Kashiwaya et al., 2013).”
From The Search for Antiaging Interventions: From Elixirs to Fasting Regimens (2014) · cites this paper as Kashiwaya et al., 2013
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- Authors
- Kashiwaya, Y., Bergman, C., Lee, J.-H., Wan, R., King, M. T., Mughal, M. R., Okun, E., Clarke, K., Mattson, M. P., & Veech, R. L.
- Affiliations
- National Institutes of Health (US)
- Konkuk University (KR)
- Bar-Ilan University (IL)
- University of Oxford (GB)
- Corresponding author
- Mattson, Mark P.
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 34
- Issue
- 6
- Pages
- 1530-1539
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3619192
- OpenAlex
- W2109421548
- Cited by
- 363
- References
- 53
- Citations by year
- 2026: 23 · 2025: 20 · 2024: 28 · 2023: 29 · 2022: 36 · 2021: 38 · 2020: 34 · 2019: 28 · 2018: 29 · 2017: 23 · 2016: 24 · 2015: 23 · 2014: 17 · 2013: 10
- FWCI
- 10.72
- 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 Programs of the National Institute on Aging
- National Institute on Alcohol Abuse and Alcoholism
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, 3xTg-AD mice, ketone bodies, amyloid-beta, tau hyperphosphorylation, anxiety, learning and memory, hippocampus, amygdala, neurofibrillary pathology, dietary intervention
- MeSH terms
- Alzheimer Disease, Animals, Anxiety, Cognition Disorders, Disease Models, Animal, Male, Mice, Inbred C57BL, Mice, Transgenic, Random Allocation, Amyloid beta-Peptides, tau Proteins, Maze Learning, Mice, Diet, Ketogenic
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