Affiliation:
1. Department of Pathology and Laboratory Medicine and Medical Investigation of Neurodevelopmental Disorders University of California Davis Medical Center Sacramento California USA
2. Medical Investigation of Neurodevelopmental Disorders Institute University of California Davis Medical Center Sacramento California USA
3. Alzheimer's Disease Research Center University of California Davis Medical Center Sacramento California USA
4. Department of Molecular Biosciences University of California, Davis Davis California USA
5. Department of Public Health Sciences University of California, Davis Davis California USA
Abstract
AbstractFatty acids are metabolized by β‐oxidation within the “mitochondrial ketogenic pathway” (MKP) to generate β‐hydroxybutyrate (BHB), a ketone body. BHB can be generated by most cells but largely by hepatocytes following exercise, fasting, or ketogenic diet consumption. BHB has been shown to modulate systemic and brain inflammation; however, its direct effects on microglia have been little studied. We investigated the impact of BHB on Aβ oligomer (AβO)‐stimulated human iPS‐derived microglia (hiMG), a model relevant to the pathogenesis of Alzheimer's disease (AD). HiMG responded to AβO with proinflammatory activation, which was mitigated by BHB at physiological concentrations of 0.1–2 mM. AβO stimulated glycolytic transcripts, suppressed genes in the β‐oxidation pathway, and induced over‐expression of AD‐relevant p46Shc, an endogenous inhibitor of thiolase, actions that are expected to suppress MKP. AβO also triggered mitochondrial Ca2+ increase, mitochondrial reactive oxygen species production, and activation of the mitochondrial permeability transition pore. BHB potently ameliorated all the above mitochondrial changes and rectified the MKP, resulting in reduced inflammasome activation and recovery of the phagocytotic function impaired by AβO. These results indicate that microglia MKP can be induced to modulate microglia immunometabolism, and that BHB can remedy “keto‐deficiency” resulting from MKP suppression and shift microglia away from proinflammatory mitochondrial metabolism. These effects of BHB may contribute to the beneficial effects of ketogenic diet intervention in aged mice and in human subjects with mild AD.
Funder
National Institute of Neurological Disorders and Stroke
National Institute on Aging
Subject
Genetics,Molecular Biology,Biochemistry,Biotechnology
Cited by
2 articles.
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