Increased glucose uptake in hippocampus as a surrogate biomarker of metabolic reconfiguration of microglia in Alzheimer's disease

Microglia is dynamically reprogrammed according to the progression of Alzheimer's disease (AD). However, clinical translation into biomarker development for functional change in microglia has not been achieved. Here, we find the close association of the metabolic reconfiguration of microglia with increased hippocampal glucose uptake, which can be noninvasively estimated by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). We found that increased FDG activity in the hippocampus of an AD mouse model depended on microglial uptake. Single-cell RNA-sequencing of the hippocampus showed the changes of glucose metabolism profiles including glucose transporters, glycolysis and oxidative phosphorylation mainly occurred in microglia. A subset of microglia with high glucose transporters with defective glycolysis and oxidative phosphorylation was increased according to disease progression. Furthermore, we also found a positive association between a soluble TREM2 of cerebrospinal fluid, a marker of microglial activation, and hippocampal FDG uptake as a human study. We identified a reconfiguration of microglial glucose metabolism in the hippocampus of AD and suggested a feasible imaging biomarker based on widely used FDG PET to reflect microglial metabolic profiles. Overall design: The purified cells obtained from the hippocampus (CA1) were sequenced using the Chromium single cell gene expression platform (10x Genomics). Approximately 1000-1500 cells from each dissected brain were directly loaded into each sample well following manufacturer instructions. All samples were combined into droplets with barcoded beads. Manufacturer specifications were followed for generation of the barcoded libraries and then the samples were sequenced to an average depth of 40,000-60,000 reads on an Illumina Nextseq 500 sequencer.