Depletion and activation of microglia impact metabolic connectivity of the mouse brain

Abstract

Aim We aimed to investigate the impact of microglial activity and microglial FDG uptake on metabolic connectivity, since microglial activation states determine FDG–PET alterations. Metabolic connectivity refers to a concept of interacting metabolic brain regions and receives growing interest in approaching complex cerebral metabolic networks in neurodegenerative diseases. However, underlying sources of metabolic connectivity remain to be elucidated. Materials and methods We analyzed metabolic networks measured by interregional correlation coefficients (ICCs) of FDG–PET scans in WT mice and in mice with mutations in progranulin (Grn) or triggering receptor expressed on myeloid cells 2 (Trem2) knockouts (−/−) as well as in double mutant Grn−/−/Trem2−/− mice. We selected those rodent models as they represent opposite microglial signatures with disease associated microglia in Grn−/− mice and microglia locked in a homeostatic state in Trem2−/− mice; however, both resulting in lower glucose uptake of the brain. The direct influence of microglia on metabolic networks was further determined by microglia depletion using a CSF1R inhibitor in WT mice at two different ages. Within maps of global mean scaled regional FDG uptake, 24 pre-established volumes of interest were applied and assigned to either cortical or subcortical networks. ICCs of all region pairs were calculated and z-transformed prior to group comparisons. FDG uptake of neurons, microglia, and astrocytes was determined in Grn−/− and WT mice via assessment of single cell tracer uptake (scRadiotracing). Results Microglia depletion by CSF1R inhibition resulted in a strong decrease of metabolic connectivity defined by decrease of mean cortical ICCs in WT mice at both ages studied (6–7 m; p = 0.0148, 9–10 m; p = 0.0191), when compared to vehicle-treated age-matched WT mice. Grn−/−, Trem2−/− and Grn−/−/Trem2−/− mice all displayed reduced FDG–PET signals when compared to WT mice. However, when analyzing metabolic networks, a distinct increase of ICCs was observed in Grn−/− mice when compared to WT mice in cortical (p < 0.0001) and hippocampal (p < 0.0001) networks. In contrast, Trem2−/− mice did not show significant alterations in metabolic connectivity when compared to WT. Furthermore, the increased metabolic connectivity in Grn−/− mice was completely suppressed in Grn−/−/Trem2−/− mice. Grn−/− mice exhibited a severe loss of neuronal FDG uptake (− 61%, p < 0.0001) which shifted allocation of cellular brain FDG uptake to microglia (42% in Grn−/− vs. 22% in WT). Conclusions Presence, absence, and activation of microglia have a strong impact on metabolic connectivity of the mouse brain. Enhanced metabolic connectivity is associated with increased microglial FDG allocation.

Systematic review of 31P-magnetic resonance spectroscopy studies of brain high energy phosphates and membrane phospholipids in aging and Alzheimer's disease

“…It is also worth noting that non-neuronal cells, such as astrocytes or microglia, may be contributing toward the detected phosphorus signals, as has been previously reported for FDG-PET (Zimmer et al, 2017;Xiang et al, 2021;Gnörich et al, 2023). However, astrocytes are more reliant on glycolysis (Chen et al, 2023), and while resting state microglia may rely on OXPHOS, they are believed to switch to primarily using glycolysis to meet energy demands under inflammatory conditions (Lauro and Limatola, 2020), whereas neurons rely more on OXPHOS unless glucose is unavailable (Hall et al, 2012;Chen et al, 2023).…”

“…As alterations in HEP metabolites, ROS, and inflammation interact in their contribution to AD risk (Wang et al, 2020 ; Billingham et al, 2022 ), future studies pairing 31 P-MRS with PET imaging will provide useful information in the development of therapeutic and preventative strategies targeting mitochondrial dysfunction in AD. It is also worth noting that non-neuronal cells, such as astrocytes or microglia, may be contributing toward the detected phosphorus signals, as has been previously reported for FDG-PET (Zimmer et al, 2017 ; Xiang et al, 2021 ; Gnörich et al, 2023 ). However, astrocytes are more reliant on glycolysis (Chen et al, 2023 ), and while resting state microglia may rely on OXPHOS, they are believed to switch to primarily using glycolysis to meet energy demands under inflammatory conditions (Lauro and Limatola, 2020 ), whereas neurons rely more on OXPHOS unless glucose is unavailable (Hall et al, 2012 ; Chen et al, 2023 ).…”

Notoginsenoside R1, a novel natural PPARγ agonist, attenuates cognitive deficits in a mouse model of diabetic Alzheimer’s disease through enhancing GLUT4-dependent neuronal glucose uptake

“…Another limitation is the lack of speci city regarding cell-speci c glucose uptake in the brain. While brain 18 F-FDG-PET is commonly believed to re ect neuronal and astrocytic glucose uptake, recent ndings suggest that activated microglia signi cantly contribute to cerebral glucose uptake (Gnörich et al, 2023;Xiang et al, 2021). The precise relationship between brain 18 F-FDG-PET and neuronal glucose uptake requires further elucidation.…”

Remote Neuroinflammation in Newly Diagnosed Glioblastoma Correlates with Unfavorable Clinical Outcome

“…MACS was performed as described previously (23, 31, 76). Detailed descriptions of brain dissociation and isolation of myeloid cells were as follows.…”