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

Journal of Neuroinflammation

Hyun Kim¹  Do Won Hwang¹  Youngsun Lee¹  Seokjun Kwon¹  Yoori Choi¹  Eun Ji Lee¹  Hongyoon Choi²  Dong Soo Lee³ 

[1] Department of Nuclear Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-Gu, 03080, Seoul, Seoul, Republic of Korea;Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, 101 Daehak-ro, Jongno-Gu, 03080, Seoul, Seoul, Republic of Korea;Department of Nuclear Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-Gu, 03080, Seoul, Seoul, Republic of Korea;Department of Nuclear Medicine, Seoul National University College of Medicine, 101 Daehak-ro, 03080, Seoul, Jongo-Gu, Republic of Korea;Department of Nuclear Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-Gu, 03080, Seoul, Seoul, Republic of Korea;Department of Nuclear Medicine, Seoul National University College of Medicine, 101 Daehak-ro, 03080, Seoul, Jongo-Gu, Republic of Korea;Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, 101 Daehak-ro, Jongno-Gu, 03080, Seoul, Seoul, Republic of Korea;

关键词: Alzheimer’s disease;    Microglia;    Positron emission tomography;    Hippocampus;    Single-cell RNA-sequencing;   

DOI  :  10.1186/s12974-021-02244-6

来源: Springer

【 摘 要 】

BackgroundDynamically 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.MethodsWe 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.ResultsIn 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.ConclusionsWe 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.

【 授权许可】

CC BY