Table 1 Summary of AD microglial omics and metabolism studies
From: Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research
Models | Sample types | Modulation | Key Findings | Screening Methods | References | |
|---|---|---|---|---|---|---|
AD animal model microglia | APP/PS1 (M,F; 16-18 M) | isolated adult mouse microglia |  | ↑ Glycolysis in females vs. males | multiplexed gene expression analysis; LC/MS | Guillot-Sestier et al. (2021) [90] |
APP/PS1 | isolated adult mouse microglia | TREM2 depletion | TREM2-dependent changes in OXPHOS & cholesterol metabolism | bulk RNA-seq; metabolomics; lipidomics | Feiten et al. (2024) [248] | |
5XFAD (M,F; 3-7 M) | isolated adult mouse microglia |  | ↑ LD accumulation, ↓ FFAs, ↑ TGs | Lipidomics | Prakash et al. (2024) [66] | |
5XFAD (-; 2,6,9Â M) | hippocampus | Â | Altered glucose metabolism (transporters, glycolysis, OXPHOS) | scRNA-seq | Choi et al. (2021) [127] | |
5XFAD (F; 9 M) | brain |  | ↑ Glycolysis, mitochondrial repurposing, ↑ proton leak | scRNA-seq | Sangineto et al. (2023) [92] | |
5XFAD (F; 7.5 M) | isolated adult mouse microglia | oAβ ICV injection | Aβ-induced acute inflammation & tolerance depend on glycolysis shift | bulk RNA-seq | Baik et al. (2019) [46] | |
5XFAD (-; 12Â M) | isolated adult mouse microglia | PKM2 inhibition | Glycolysis/H4K12la/PKM2 positive feedback loop exacerbates microglial dysfunction | genome-wide CUT&Tag analysis | Pan et al. (2022) [114] | |
5XFAD (M,F; 1,3,6,8 M) | isolated adult mouse microglia | TREM2 depletion | TREM2 required for full DAM activation (↑ phagocytosis & lipid metabolism) | scRNA-seq; ChiP | Keren-Shaul et al. (2017) [157] | |
5XFAD (F; 8) | isolated adult mouse microglia, BMDM | TREM2 depletion | TREM2 loss → AMPK-driven autophagy, ↓ anabolic & energetic metabolism | Microarray; EIS-MS/MS | Ulland et al. (2017) [35] | |
5XFAD (M,F; 7,15 M) | brain | TREM2 depletion | ↓ Microglia-expressed protein abundance in Trem2–/– | snRNA-seq; proteomics | Zhou et al. (2020) [253] | |
5XFADiPKR; 5XFADEif2A (M, F; 6Â M); PS19iPKR; PS19Eif2A (M,F; 8Â M) | isolated adult mouse microglia; Microglia-specific ribosomal profiling (TRAP) | microglia specific ISR modulation | Glycolytic & lipid metabolism changes, toxic lipid secretion | snRNA-seq; TRAP seq | Flurry et al. (2024) [196] | |
5XFAD; hAPOE (-; 2,24 M) | brain | human APOE2, APOE3, APOE4 KI | TIM depletion in cellular energetics (TCA cycle, glycolysis, PPP); ↑ ROS detox pathways & amino acid metabolism | scRNA-seq/scATAC-seq multiome; interactome | Millet et al. (2024) [259] | |
hAPOE KI (F; 3,12,24 M) | region-specific | human APOE3, APOE4 KI | APOE4 microglia: ↑ Aerobic glycolysis, ↑ Hif1α, altered lipid metabolism | snRNA-seq; spatial transcriptomics; metabolomics | Lee et al. (2023) [70] | |
hAPOE KI; P301S:hAPOE KI; APP/PS1:hAPOE KI | brain; isolated adult mouse microglia | human APOE3, APOE4 KI and conditional KO; LGALS3 stereotaxic injection; Inpp5d modulation; ITGB8 inhibition | APOE4-ITGB8-TGFβ as a negative regulator of MGnD response; altered lipid species | scRNA-seq; ChIP-seq; lipidomics | Yin et al. (2023) [256] | |
P301S:hAPOE KI; P301S:APOE KO (male; 9 M) | hippocampus; BMDM | TREM2 depletion | ApoE4 & tau-associated microgliosis → TREM2-independent lysosomal lipid accumulation | snRNA-seq (FANS) | Gratuze et al. (2023) [274] | |
APP NL-G-F (M,F; 9 M) | isolated adult mouse microglia; primary microglia | C3aRKO | C3aR + microglia: dysfunctional metabolism; C3aR1-null microglia resistant to hypoxia-induced lipid accumulation; C3aR ablation rescued lipid profiles & improved phagocytosis | bulk RNA-seq | Gedam et al. (2023) [309] | |
APPSAA (M,F; 5-20 M) | isolated adult mouse microglia; brain biofluid |  | Microglia with high intracellular Aβ → significant lipid & metabolite changes | bulk RNA-seq; LC/MS | Xia et al. (2022) [48] | |
SHR24 (-; 4,6,8,10,12,14 M) | brain, CSF, plasma | Pathological tau | ↑ lipid production (protein fibrillization, membrane reorganization, inflammation); ↑ phospholipids, sphingolipids, & LD accumulation in microglia | Lipidomics | Olesova et al. (2024) [47] | |
Human iPSC-derived microglia | iPSC-derived microglia | iPSC-derived microglia | TREM2-R47H variants | ↓ OXPHOS & glycolysis; fails to switch to glycolysis after immune stimulation | Microarray; proteom array | Piers et al. (2020) [250] |
iPSC-derived microglia |  | PSEN1ΔE9, APPswe, and APOE4 | APOE4 → defective glycolytic & mitochondrial metabolism | bulk RNA-seq | Konttinen et al. (2019) [257] | |
iPSC-derived microglia | APOE3, APOE4; LD-high, LD-low | fAβ | ↑ LD accumulation, exacerbated by APOE4; LD spectra overlap with unsaturated TGs | bulk RNA-seq; ATAC-seq lipidomics | Haney et al. (2024) [260] | |
iPSC-derived microglia and neuron (spheroid) | APOE3, APOE4 | neuronal conditioned medium | APOE4 → impaired lipid catabolism & lipid accumulation | bulk RNA-seq | Victor et al. (2022) [73] | |
iPSC-derived microglia | APOE2, APOE3, APOE4, APOE KO | LDLR, CE | Altered cholesterol metabolism & lipid peroxidation | LCMS; RNA-seq | Guo et al. (2025) [283] | |
Human postmortem brain | AD-APOE4/4; AD-APOE3/3 | frontal cortex |  | ↑ LD accumulation, exacerbated by APOE4 | snRNA-seq | Haney et al. (2024) [260] |
TREM2 variant carriers (R47H, R62H) | prefrontal cortex |  | TREM2-R47H → ↑ oxidative stress & lipid metabolism genes | snRNA-seq | Zhou et al. (2020) [253] | |
AD-E4 patients, TREM2 variant carriers (R47H, R62H) | parietal cortex |  | APOE4 & tau → TREM2-independent lysosomal lipid accumulation | snRNA-seq | Gratuze et al. (2023) [274] | |
AD-APOE3/4; AD-APOE3/3 | brain |  | APOE4-ITGB8-TGFβ pathway inhibits MGnD response; lipid species alterations | bulk RNA-seq | Yin et al. (2023) [256] | |
ROSMAP | region-specific |  | ↑ Glycogen-related gene expression → glial metabolic response may not be globally coordinated | snRNA-seq | Mathys et al. (2024) [357] | |
|  | AD-E3, E4 patients; | frozen superior frontal gyrus and fusiform gyrus |  | ↑ Lipid accumulation | snRNA-seq | Haney et al. (2024) [260] |
Xenotransplantation | 5X-hCSF1 (F, 7 M) | TREM2-R47H xenografted microglia | iPSC-derived TREM2-R47H microglia transplantation | TREM2-R47H xMGs → ↓ LD accumulation & ↓ lipid metabolism genes (SPP1, APOE, CTSD) | scRNA-seq | Claes et al. (2021) [158] |
APPNL-G-F;hCSF1 | isolated microglia | iPSC-derived isogenic APOE microglia transplantation | Dysregulated lipid metabolism; ↓ CHCHD2 (mitochondrial migration gene) | bulk RNA-seq; ATAC-seq | Murphy et al. (2024) [261] | |