Effects of a dietary ketone ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTg AD mouse model of Alzheimer's disease
Open accessAbstract
In patients with Alzheimer's disease (AD) and in a triple transgenic (3xTg AD) mouse model of AD low glucose metabolism in the brain precedes loss of memory and cognitive decline. The metabolism of ketones in the brain by‐passes glycolysis and therefore may correct several deficiencies that are associated with glucose hypometabolism. A dietary supplement composed of an ester of D‐β‐hydroxybutyrate and R‐1,3 butane diol referred to as ketone ester (KE) was incorporated into a rodent diet and fed to 3xTg AD mice for 8 months. At 16.5 months of age animals were killed and brains dissected. Analyses were carried out on the hippocampus and frontal cortex for glycolytic and TCA (Tricarboxylic Acid) cycle intermediates, amino acids, oxidized lipids and proteins, and enzymes. There were higher concentrations of d‐β‐hydroxybutyrate in the hippocampus of KE‐fed mice where there were also higher concentrations of TCA cycle and glycolytic intermediates and the energy‐linked biomarker, N‐acetyl aspartate compared to controls. In the hippocampi of control‐fed animals the free mitochondrial [NAD+]/[NADH] ratio were highly oxidized, whereas, in KE‐fed animals the mitochondria were reduced. Also, the levels of oxidized protein and lipids were lower and the energy of ATP hydrolysis was greater compared to controls. 3xTg AD mice maintained on a KE‐supplemented diet had higher concentrations of glycolytic and TCA cycle metabolites, a more reduced mitochondrial redox potential, and lower amounts of oxidized lipids and proteins in their hippocampi compared to controls. The KE offers a potential therapy to counter fundamental metabolic deficits common to patients and transgenic models. image Read the Editorial Highlight for this article on page 162.
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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 Pawlosky et al., 2017
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- Authors
- Pawlosky, R. J., Kemper, M. F., Kashiwaya, Y., King, M. T., Mattson, M. P., & Veech, R. L.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Pawlosky, Robert J.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2017-03-15
- Volume
- 141
- Issue
- 2
- Pages
- 195-207
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC5383517
- OpenAlex
- W2576775595
- Cited by
- 108
- References
- 43
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 8 · 2023: 9 · 2022: 17 · 2021: 11 · 2020: 18 · 2019: 12 · 2018: 8 · 2017: 5
- FWCI
- 8.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism
- National Institute on Aging
- Topics
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- ketone esters, Alzheimer's disease, hippocampus, glycolysis, TCA cycle, D-β-hydroxybutyrate, N-acetylaspartate, mitochondrial redox potential, oxidative stress, oxidized lipids, oxidized proteins, brain glucose metabolism, dietary supplementation, ATP hydrolysis
- MeSH terms
- Alzheimer Disease, Amino Acids, Animals, Butanes, Citric Acid Cycle, Disease Models, Animal, Glycolysis, Hippocampus, Hydroxybutyrates, Ketone Bodies, Male, Mice, Inbred C57BL, Mice, Transgenic, Mice, Diet, Ketogenic
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