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Brain Endothelial Cells Utilize Glycolysis for the Maintenance of the Transcellular Permeability

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Abstract

Among the components of the blood–brain barrier (BBB), endothelial cells (ECs) play an important role in supplying limited materials, especially glucose, to the brain. However, the mechanism by which glucose is metabolized in brain ECs is still elusive. To address this topic, we assessed the metabolic signature of glucose utilization using live-cell metabolic assays and liquid chromatography–tandem mass spectrometry metabolomic analysis. We found that brain ECs are highly dependent on aerobic glycolysis, generating lactate as its final product with minimal consumption of glucose. Glucose treatment decreased the oxygen consumption rate in a dose-dependent manner, indicating the Crabtree effect. Moreover, when glycolysis was inhibited, brain ECs showed impaired permeability to molecules utilizing transcellular pathway. In addition, we found that the blockade of glycolysis in mouse brain with 2-deoxyglucose administration resulted in decreased transcellular permeability of the BBB. In conclusion, utilizing glycolysis in brain ECs has critical roles in the maintenance and permeability of the BBB. Overall, we could conclude that brain ECs are highly glycolytic, and their energy can be used to maintain the transcellular permeability of the BBB.

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Funding

This research was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, and ICT (NRF- 2021R1C1C1011427 to D.G. Kim) and KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (21-BR-02–17 to D.G. Kim), and Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare (H I14C1135).

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Authors and Affiliations

  1. Neuroimmunology Lab, Dementia Research Group, Korea Brain Research Institute, Daegu, Donggu, 41062, South Korea

    Eun Seon Kim, Kyu-Sung Kim, Chan Hee Lee, Min-Tae Jeon & Do-Geun Kim

  2. Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, Republic of Korea

    Eun Seon Kim, Kyu-Sung Kim & Sung Bae Lee

  3. Analyitical Chemistry Center, Korea Institute of Toxicology, Daejeon, South Korea

    Jong Hwa Lee

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  1. Eun Seon Kim
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  2. Kyu-Sung Kim
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Contributions

ESK, CHL, KSK, MTJ, JHL, and DGK performed experiments. DGK designed studies and conceptualized experiments. ESK, JHL, and DGK analyzed data and wrote manuscripts. JHL and DGK secured funding for this study.

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Correspondence to Jong Hwa Lee or Do-Geun Kim.

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Ethics Approval

This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Institutional Animal Care and Use Committee of Korea Brain Research Institute (IACUC-17–00002, IACUC-17–00012).

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Kim, E.S., Kim, KS., Lee, C.H. et al. Brain Endothelial Cells Utilize Glycolysis for the Maintenance of the Transcellular Permeability. Mol Neurobiol 59, 4315–4333 (2022). https://doi.org/10.1007/s12035-022-02778-7

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