Prophylactic Beta-Hydroxybutyrate for Alzheimer’s Disease and Atherosclerosis

by | May 5, 2020 | 2020, Alzheimer's Disease, Brain Health, Cardiovascular Health

Written by Angeline A. De Leon, Staff Writer. This study explores the anti-inflammatory capability of beta-hydroxybutyrate (β-OHB) and the mechanism by which it protects against Alzheimer’s disease (AD) and atherosclerosis.

agingAs the number of annual cases of dementia and AD continues to soar worldwide, research efforts have focused on more preventative strategies, such as nutritional therapies and other lifestyle interventions 1. Apolipoprotein-E (ApoE), a protein involved in the metabolism of fat and cholesterol homeostasis 2, has been directly linked to the regulation of the immune system 3 and is known to play a critical role in inflammation-related diseases, including both AD and atherosclerosis 4,5. β-OHB, a key component of ketone bodies (byproducts of fat burning in the body), has demonstrated protective effects against cognitive impairment 6,7, as well as other types of neurological disorders 8. Although further research is needed to understand the common mechanism of action regarding β-OHB’s therapeutic effects in both AD and atherosclerosis, an anti-inflammatory function is hypothesized, based on evidence for β-OHB’s inhibitory effect on inflammasome pathways 9.  In a 2020 study 10 published in Nutrients, researchers in Korea explored the therapeutic impact of β-OHB in ApoE-deficient (atherosclerosis prone) mice, looking at inflammatory processes and lipid accumulation in the brain and atherosclerotic plaque formation in the arteries.

The experimental protocol involved six-week-old ApoE-deficient male mice, 10 of which were fed a normal chow diet (NCD) and 20 of which were fed a high-fat diet (HFD) for 8 weeks. HFD mice were subcutaneously implanted with osmotic minipumps and then randomly divided into two groups, half receiving saline through the minipumps and the other half receiving β-OHB (1.5 mmol/kg/day) for 8 weeks. Animals were sacrificed and aortic and whole brain tissue samples harvested. A mouse cell line derived from tissue of the choroid plexus (ChP, brain region involved in production of cerebrospinal fluid) was obtained and analyzed for relative gene expression using quantitative real-time polymerase chain reaction. Amyloid plaque formation (associated with AD) was measured in brain tissue using immunofluorescence and immunohistochemistry techniques, and total lipid deposits at the aortic root and ChP regions were quantified using a staining technique.

Analyses showed that treatment with β-OHB attenuated HFD-induced lipid deposition (percentage of lipid deposit) in ChP regions (p < 0.001) and reduced plaque formation in the substantia nigra pars compacta (SNR, involved in modulation of motor movement and reward), relative to control mice. Mice receiving β-OHB treatment also exhibited reduced expression of CD68 macrophage (marker of inflammation) (based on fold increase of CD68-positive staining) in ChP regions, as compared to control mice (p < 0.001). Treatment with β-OHB vs. placebo was also associated with about a 60% reduction in atherosclerotic plaque deposits in the aorta (p < 0.001) and was shown to significantly reduce serum levels of resistin, a risk factor associated with both AD and atherosclerosis 11,12 (p < 0.05).

In all, evidence from the study points to a protective role of β-OHB in a rodent model of AD and atherosclerosis. β-OHB treatment appears to attenuate inflammatory reactions in the ChP region and inhibit plaque formation and lipid deposition in the aorta. Researchers also found that β-OHB was associated with reduced serum levels of resistin, common to both AD and atherosclerosis, suggesting that β-OHB may be an effective therapeutic treatment for both neurodegenerative and cardiovascular diseases. Based on findings, it is suggested that a common mode of action for β-OHB in both diseases may be related to an anti-inflammatory function. Overall, exogenous β-OHB supplementation represents a promising therapeutic approach for both AD and atherosclerosis. Translational research in human subjects is warranted.

Krishnan M, Hwang JS, Kim M, et al. Β-hydroxybutyrate impedes the progression of Alzheimer’s disease and atherosclerosis in ApoE-Deficient Mice. Nutrients. 2020; 12: 471. DOI: 10.3390/nu12020471.

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Click here to read the full text study.

Posted May 5, 2020.

Angeline A. De Leon, MA, graduated from the University of Illinois at Urbana-Champaign in 2010, completing a bachelor’s degree in psychology, with a concentration in neuroscience. She received her master’s degree from The Ohio State University in 2013, where she studied clinical neuroscience within an integrative health program. Her specialized area of research involves the complementary use of neuroimaging and neuropsychology-based methodologies to examine how lifestyle factors, such as physical activity and meditation, can influence brain plasticity and enhance overall connectivity. http://www.naturalhealthresearch.org/wp-content/uploads/2017/10/Angeline.jpg

References:

  1. Mendiola-Precoma J, Berumen LC, Padilla K, Garcia-Alcocer G. Therapies for Prevention and Treatment of Alzheimer’s Disease. Biomed Res Int. 2016;2016:2589276.
  2. Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. Journal of molecular medicine (Berlin, Germany). 2016;94(7):739-746.
  3. Yin C, Ackermann S, Ma Z, et al. ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med. 2019;25(3):496-506.
  4. Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron. 2014;81(4):740-754.
  5. Linton MF, Atkinson JB, Fazio S. Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation. Science. 1995;267(5200):1034-1037.
  6. Taylor MK, Swerdlow RH, Sullivan DK. Dietary Neuroketotherapeutics for Alzheimer’s Disease: An Evidence Update and the Potential Role for Diet Quality. Nutrients. 2019;11(8).
  7. Fortier M, Castellano CA, Croteau E, et al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimer’s & dementia : the journal of the Alzheimer’s Association. 2019;15(5):625-634.
  8. Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. d-β-Hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proceedings of the National Academy of Sciences. 2000;97(10):5440-5444.
  9. Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21(3):263-269.
  10. Krishnan M, Hwang JS, Kim M, et al. β-hydroxybutyrate Impedes the Progression of Alzheimer’s Disease and Atherosclerosis in ApoE-Deficient Mice. Nutrients. 2020;12(2).
  11. Misiak B, Leszek J, Kiejna A. Metabolic syndrome, mild cognitive impairment and Alzheimer’s disease–the emerging role of systemic low-grade inflammation and adiposity. Brain research bulletin. 2012;89(3-4):144-149.
  12. Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation. 2005;111(7):932-939.