Abstract

Therapeutic interventions are greatly needed for age-related neurodegenerative diseases. Astrocytes regulate many aspects of neuronal function including bioenergetics and synaptic transmission. Reactive astrocytes are implicated in neurodegenerative diseases due to their pro-inflammatory phenotype close association with damaged neurons. Thus, strategies to reduce astrocyte reactivity may support brain health. Caloric restriction and a ketogenic diet limit energy production via glycolysis and promote oxidative phosphorylation, which has gained traction as a strategy to improve brain health. However, it is unknown how caloric restriction affects astrocyte reactivity in the context of neuroinflammation. We investigated how a caloric restriction mimetic and glycolysis inhibitor, 2-deoxyglucose (2-DG), affects interleukin 1β-induced inflammatory gene expression in human astrocytes. Human astrocyte cultures were exposed to 2-DG or vehicle for 24 h and then to recombinant IL-1β for 6 or 24 h to analyze mRNA and protein expression, respectively. Gene expression levels of proinflammatory genes (complement component 3, IL-1β, IL6, and TNFα) were analyzed by real-time PCR, immunoblot, and immunohistochemistry. As expected, IL-1β induced elevated levels of proinflammatory genes. 2-DG reversed this effect at the mRNA and protein levels without inducing cytotoxicity. Collectively, these data suggest that inhibiting glycolysis in human astrocytes reduces IL-1β-induced reactivity. This finding may lead to novel therapeutic strategies to limit inflammation and enhance bioenergetics toward the goal of preventing and treating neurodegenerative diseases.

Highlights

  • We have discovered evidence that reactive astrocytes cause a reduction in the levels of transcription factor at mitochondria (TFAM) in neurons that results in deficient mitochondrial biogenesis [8,9]

  • We found that the caloric restriction mimetic and glycolytic inhibitor 2-deoxyglucose inhibits IL-1β-induced inflammatory gene expression in a dose-dependent manner

  • Primary human astrocyte cultures were pretreated with tally inhibit glycolysis

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Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The world’s aging population is susceptible to age-related neurodegenerative diseases, for many of which no effective preventive therapies or treatments are available. Neuroinflammation is a hallmark of many neurodegenerative diseases and represents a potential therapeutic target to improve the health and quality of life of aging populations [1,2]. Microglia and astrocytes produce and perpetuate neuroinflammation in the brain and are believed to contribute to neurodegeneration when in a chronically reactive state [3,4,5,6,7]

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