Hippocampal glucose uptake as a surrogate of metabolic change of microglia in Alzheimer’s disease

Abstract

Background Dynamically altered microglia play an important role in the progression of Alzheimer’s disease (AD). Here, we found a close association of the metabolic reconfiguration of microglia with increased hippocampal glucose uptake on [18F]fluorodeoxyglucose (FDG) PET. Methods We used an AD animal model, 5xFAD, to analyze hippocampal glucose metabolism using both animal FDG PET and ex vivo FDG uptake test. Cells of the hippocampus were isolated to perform single-cell RNA-sequencing (scRNA-seq). The molecular features of cells associated with glucose metabolism were analyzed at a single-cell level. In order to apply our findings to human brain imaging study, brain FDG PET data obtained from the Alzheimer’s Disease Neuroimaging Initiative were analyzed. FDG uptake in the hippocampus was compared according to the diagnosis, AD, mild cognitive impairment, and controls. The correlation analysis between hippocampal FDG uptake and soluble TREM2 in cerebrospinal fluid was performed. Results In the animal study, 8- and 12-month-old 5xFAD mice showed higher FDG uptake in the hippocampus than wild-type mice. Cellular FDG uptake tests showed that FDG activity in hippocampal microglia was increased in the AD model, while FDG activity in non-microglial cells of the hippocampus was not different between the AD model and wild-type. scRNA-seq data showed that changes in glucose metabolism signatures including glucose transporters, glycolysis and oxidative phosphorylation, mainly occurred in microglia. A subset of microglia with higher glucose transporters with defective glycolysis and oxidative phosphorylation was increased according to disease progression. In the human imaging study, we found a positive association between soluble TREM2 and hippocampal FDG uptake. FDG uptake in the hippocampus at the baseline scan predicted mild cognitive impairment conversion to AD. Conclusions We identified the reconfiguration of microglial glucose metabolism in the hippocampus of AD, which could be evaluated by FDG PET as a feasible surrogate imaging biomarker for microglia-mediated inflammation.

An orally active apelin receptor agonist improves Alzheimer’s disease pathology and cognitive functions by restoring microglial metabolism

“…In our study, the reduction in 2-NBDG uptake in the hippocampus of total cells and hippocampal CD11b + microglia of 5xFAD mice indicates that microglial metabolic dysfunction accompanies AD pathology. At first glance, our findings appear to contrast with studies demonstrating increased glucose uptake in activated microglia [46]. Indeed, acute exposure to inflammatory stimuli such as lipopolysaccharide (LPS) or Aβ induces rapid metabolic reprogramming characterised by enhanced glucose uptake, increased glycolytic flux, and elevated FDG accumulation [9].…”

An orally active apelin receptor agonist improves Alzheimer’s disease pathology and cognitive functions by restoring microglial metabolism

“…In our study, the reduction in 2-NBDG uptake in the hippocampus of total cells and hippocampal CD11b + microglia of 5xFAD mice indicates that microglial metabolic dysfunction accompanies AD pathology. At first glance, our findings appear to contrast with studies demonstrating increased glucose uptake in activated microglia [46]. Indeed, acute exposure to inflammatory stimuli such as lipopolysaccharide (LPS) or Aβ induces rapid metabolic reprogramming characterised by enhanced glucose uptake, increased glycolytic flux, and elevated FDG accumulation [9].…”

Fueling Alzheimer’s Disease: Where Does Immunometabolism Stand?

“…Remarkably, scRNA-seq data showed that changes in glucose metabolism signature including glucose transporters, glycolysis and OXPHOS, mainly occurred in microglia in this preclinical model. That said, this data suggests a reconfiguration of microglial glucose metabolism in the hippocampus during the course of AD pathology 162 …”

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer’s disease

“…In male 5xFAD mice at 12 months, virtually every region tested exhibited metabolic reductions (Franke et al, 2020) and this was also reported in female 5xFAD mice (Bouter et al, 2021). Alternatively, Choi et al (2021) reported increased hippocampal 18 F-FDG uptake compared to WT at 4, 8, and 12 months of age. The contrasting findings could in part, be explained by methodological differences (glucose correction, ligand injection in anesthetized or awake mouse, normalization method, etc.…”

An orally active apelin receptor agonist improves Alzheimer’s disease pathology and cognitive functions by restoring microglial metabolism

“…In our study, the reduction in 2-NBDG uptake in the hippocampus of total cells and hippocampal CD11b + microglia of 5xFAD mice indicates that microglial metabolic dysfunction accompanies AD pathology. At first glance, our findings appear to contrast with studies demonstrating increased glucose uptake in activated microglia [46]. Indeed, acute exposure to inflammatory stimuli such as lipopolysaccharide (LPS) or Aβ induces rapid metabolic reprogramming characterised by enhanced glucose uptake, increased glycolytic flux, and elevated FDG accumulation [9].…”

Fueling Alzheimer’s Disease: Where Does Immunometabolism Stand?

“…Remarkably, scRNA-seq data showed that changes in glucose metabolism signature including glucose transporters, glycolysis and OXPHOS, mainly occurred in microglia in this preclinical model. That said, this data suggests a reconfiguration of microglial glucose metabolism in the hippocampus during the course of AD pathology 162 …”

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer’s disease

“…In male 5xFAD mice at 12 months, virtually every region tested exhibited metabolic reductions (Franke et al, 2020) and this was also reported in female 5xFAD mice (Bouter et al, 2021). Alternatively, Choi et al (2021) reported increased hippocampal 18 F-FDG uptake compared to WT at 4, 8, and 12 months of age. The contrasting findings could in part, be explained by methodological differences (glucose correction, ligand injection in anesthetized or awake mouse, normalization method, etc.…”

An orally active apelin receptor agonist improves Alzheimer’s disease pathology and cognitive functions by restoring microglial metabolism

“…In our study, the reduction in 2-NBDG uptake in the hippocampus of total cells and hippocampal CD11b + microglia of 5xFAD mice indicates that microglial metabolic dysfunction accompanies AD pathology. At first glance, our findings appear to contrast with studies demonstrating increased glucose uptake in activated microglia [46]. Indeed, acute exposure to inflammatory stimuli such as lipopolysaccharide (LPS) or Aβ induces rapid metabolic reprogramming characterised by enhanced glucose uptake, increased glycolytic flux, and elevated FDG accumulation [9].…”

Fueling Alzheimer’s Disease: Where Does Immunometabolism Stand?

“…Remarkably, scRNA-seq data showed that changes in glucose metabolism signature including glucose transporters, glycolysis and OXPHOS, mainly occurred in microglia in this preclinical model. That said, this data suggests a reconfiguration of microglial glucose metabolism in the hippocampus during the course of AD pathology 162 …”

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer’s disease

“…In male 5xFAD mice at 12 months, virtually every region tested exhibited metabolic reductions (Franke et al, 2020) and this was also reported in female 5xFAD mice (Bouter et al, 2021). Alternatively, Choi et al (2021) reported increased hippocampal 18 F-FDG uptake compared to WT at 4, 8, and 12 months of age. The contrasting findings could in part, be explained by methodological differences (glucose correction, ligand injection in anesthetized or awake mouse, normalization method, etc.…”