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Acute glucose fluctuation impacts microglial activity, leading to inflammatory activation or self-degradation.

ABSTRACT: Diabetes mellitus is associated with an increased risk of Alzheimer's dementia and cognitive decline. The cause of neurodegeneration in chronic diabetic patients remains unclear. Changes in brain microglial activity due to glycemic fluctuations may be an etiological factor. Here, we examined the impact of acute ambient glucose fluctuations on BV-2 microglial activity. Biochemical parameters were assayed and showed that the shift from normal glucose (NG; 5.5?mM) to high glucose (HG; 25?mM) promoted cell growth and induced oxidative/inflammatory stress and microglial activation, as evidenced by increased MTT reduction, elevated pro-inflammatory factor secretion (i.e., TNF-? and oxygen free radicals), and upregulated expression of stress/inflammatory proteins (i.e., HSP70, HO-1, iNOS, and COX-2). Also, LPS-induced inflammation was enlarged by an NG-to-HG shift. In contrast, the HG-to-NG shift trapped microglia in a state of metabolic stress, which led to apoptosis and autophagy, as evidenced by decreased Bcl-2 and increased cleaved caspase-3, TUNEL staining, and LC3B-II expression. These stress episodes were primarily mediated through MAPKs, PI3K/Akt, and NF-?B cascades. Our study demonstrates that acute glucose fluctuation forms the stress that alters microglial activity (e.g., inflammatory activation or self-degradation), representing a novel pathogenic mechanism for the continued deterioration of neurological function in diabetic patients.

SUBMITTER: Hsieh CF

PROVIDER: S-EPMC6351546 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Acute glucose fluctuation impacts microglial activity, leading to inflammatory activation or self-degradation.

Hsieh Cheng-Fang CF Liu Ching-Kuan CK Lee Ching-Tien CT Yu Liang-En LE Wang Jiz-Yuh JY

Scientific reports 20190129 1

Diabetes mellitus is associated with an increased risk of Alzheimer's dementia and cognitive decline. The cause of neurodegeneration in chronic diabetic patients remains unclear. Changes in brain microglial activity due to glycemic fluctuations may be an etiological factor. Here, we examined the impact of acute ambient glucose fluctuations on BV-2 microglial activity. Biochemical parameters were assayed and showed that the shift from normal glucose (NG; 5.5 mM) to high glucose (HG; 25 mM) promot ...[more]

PMID: 30696869

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Project description:BackgroundUncontrolled microglial activation contributes to the pathogenesis of various neurodegenerative diseases. Previous studies have shown that proinflammatory microglia are powered by glycolysis, which relays on high levels of glucose uptake. This study aimed to understand how glucose uptake is facilitated in active microglia and whether microglial activation can be controlled by restricting glucose uptake.MethodsPrimary murine brain microglia, BV2 cells and the newly established microglial cell line B6M7 were treated with LPS (100?ng/ml)?+?IFN? (100?ng/ml) or IL-4 (20?ng/ml) for 24?h. The expression of glucose transporters (GLUTs) was examined by PCR and Western blot. Glucose uptake by microglia was inhibited using the GLUT1-specific inhibitor STF31. The metabolic profiles were tested using the Glycolysis Stress Test and Mito Stress Test Kits using the Seahorse XFe96 Analyser. Inflammatory gene expression was examined by real-time RT-PCR and protein secretion by cytokine beads array. The effect of STF31 on microglial activation and neurodegeneraion was further tested in a mouse model of light-induced retinal degeneration.ResultsThe mRNA and protein of GLUT1, 3, 4, 5, 6, 8, 9, 10, 12, and 13 were detected in microglia. The expression level of GLUT1 was the highest among all GLUTs detected. LPS?+?IFN? treatment further increased GLUT1 expression. STF31 dose-dependently reduced glucose uptake and suppressed Extracellular Acidification Rate (ECAR) in naïve, M(LPS?+?IFN?) and M(IL-4) microglia. The treatment also prevented the upregulation of inflammatory cytokines including TNF?, IL-1?, IL-6, and CCL2 in M(LPS?+?IFN?) microglia. Interestingly, the Oxygen Consumption Rates (OCR) was increased in M(LPS?+?IFN?) microglia but reduced in M(IL-4) microglia by STF31 treatment. Intraperitoneal injection of STF31 reduced light-induced microglial activation and retinal degeneration.ConclusionGlucose uptake in microglia is facilitated predominately by GLUT1, particularly under inflammatory conditions. Targeting GLUT1 could be an effective approach to control neuroinflammation.

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Acute glucose fluctuation impacts microglial activity, leading to inflammatory activation or self-degradation.

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Acute glucose fluctuation impacts microglial activity, leading to inflammatory activation or self-degradation.

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