1. Academic Validation
  2. Imbalance in glucose metabolism regulates the transition of microglia from homeostasis to Disease Associated Microglia stage 1

Imbalance in glucose metabolism regulates the transition of microglia from homeostasis to Disease Associated Microglia stage 1

  • J Neurosci. 2024 Apr 16:e1563232024. doi: 10.1523/JNEUROSCI.1563-23.2024.
Yuxi Liu 1 Witty Kwok 1 Hyojung Yoon 2 Jae Cheon Ryu 1 Patrick Stevens 3 Tara R Hawkinson 4 5 Cameron J Shedlock 4 5 Roberto A Ribas 4 5 Terrymar Medina 4 5 Shannon B Keohane 4 5 Douglas Scharre 6 Lei Bruschweiler-Li 7 Rafael Bruschweiler 7 Alban Gaultier 8 Karl Obrietan 2 Ramon C Sun 4 5 Sung Ok Yoon 9
Affiliations

Affiliations

  • 1 Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, USA.
  • 2 Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
  • 3 Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
  • 4 Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
  • 5 Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, 32610, USA.
  • 6 Department of Neurology, The Ohio State University, Columbus, OH, USA.
  • 7 Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
  • 8 Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, 22908, USA.
  • 9 Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, USA. Sung.yoon@osumc.edu.
Abstract

Microglia undergo two-stage activation in neurodegenerative diseases, known as disease-associated microglia (DAM). TREM2 mediates the DAM2 stage transition, but what regulates the first DAM1 stage transition is unknown. We report that glucose dyshomeostasis inhibits DAM1 activation, and PKM2 plays a role. As in tumors, PKM2 was aberrantly elevated in both male and female human AD brains, but unlike in tumors, it is expressed as active tetramers, as well as among TREM2+ microglia surrounding plaques in 5XFAD male and female mice. snRNAseq analyses of microglia without Pkm2 in 5XFAD mice revealed significant increases in DAM1 markers in a distinct 'metabolic' cluster, which is enriched in genes for glucose metabolism, DAM1, and AD risk. 5XFAD mice incidentally exhibited a significant reduction in amyloid pathology without microglial Pkm2 Surprisingly, microglia in 5XFAD without Pkm2 exhibited increases in glycolysis and spare respiratory capacity, which correlated with restoration of mitochondrial cristae alterations. In addition, in situ spatial metabolomics of plaque-bearing microglia revealed an increase in respiratory activity. These results together suggest that it is not only glycolytic but also respiratory inputs that are critical to the development of DAM signatures in 5XFAD mice.Significance Statement Although reduced glucose uptake in the brain has been recognized as one of the earliest pathological events that accompany Alzheimer's disease (AD), it has not been clear whether this was due to a brain-wide defect in glucose metabolism or a dysfunction in a particular cell type. Our data suggest that dysregulation of metabolic homeostasis in microglia is critical for global AD pathology in a mouse model. Upon restoring glucose metabolism in microglia genetically, AD pathology is attenuated with a concomitant increase in DAM genes, especially DAM1 genes. These results suggest that this increase in DAM gene expression is protective against AD pathology, and glucose dyshomeostasis is a trigger to inhibit expression of protective DAM genes in AD.

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