Table 1 Summary of key metabolic processes that guide microglia function in neurodegenerative diseases

Glycolysis

Upregulation of Glut1 mRNA levels and enhanced glucose uptake following exposure to α- SYN

PD

Qiao et al. [160]

Decreased GLUT1 and GLUT3 expression, and microglial activity

AD

Biswas et al. [34]

Decreased brain glucose metabolism in PET studies, downregulation of G6P and 6-PGD levels, and increased microglial activation

PD

Dunn et al. [156]

Knockout of hexokinase 2 in microglia reduces glycolytic activity, inhibits their repopulation, and diminishes their ability to migrate in response to damage

AD

Hu et al. [215]

Increased levels of LDH-B, pyruvate kinase, and glyceraldehyde 3-phosphate dehydrogenase in astrocytes and microglia

AD

Johnson et al. [38]

A positive feedback loop involving glycolysis, H4K12 lactylation, and PKM2 in microglia contributes to the pathogenesis of AD

AD

Pan et al. [49]

Aβ and α-SYN induce metabolic reprogramming of microglia from OXPHOS to aerobic glycolysis

AD and PD

Lu et al. [163].

Baik et al. [45]

Neuroprotective effects of pyruvate on striatal neurons encompass the suppression of microglial activation

HD

Ryu et al. [193]

TREM2

Enhances mTOR signaling, facilitates the transition of microglia to a fully mature disease-associated microglia profile

AD

Ulland et al. [55]

Keren-Shaul et al.[51]

Trem2 knockout reduced ATP content and the expression of different metabolites such as D- glucose, GDP-glucose, fumarate, succinate, itaconate, ribosomal proteins, and HIF-1α

mTOR/HIF-1α pathways play a role in the induction of aerobic glycolysis caused by CLK1 deficiency

PD

Gu et al. [166]

TREM2 is highly expressed in microglia in both mouse models of the disease and in lipid-laden microglia within human MS lesions

MS

Piccio et al. [127]

Takahashi et al. [130]

Trem2 knockout in CD4 + T cells reduces Th17 cell infiltration and inflammatory cytokine production

MS

Qu et al. [128]

Lipids

Genetic risk factors for AD associated with microglia lipid droplet accumulation

AD

Haney et al. [216]

Activated microglia exhibit a preference for lipids as a fuel source to meet their increased metabolic energy demands

AD

Keren-Shaul et al. [51]

Cholesterol oxidation products such as 7-keto-cholesterol induce neuronal damage by promoting a proinflammatory microglial phenotype

MS

McComb et al. [121]

Diestel et al. [122]

Omega-3 polyunsaturated fatty promote anti-inflammatory phenotype in microglia

AD

Hopperton et al. [217]

Ketogenic diet suppresses microglial activation and attenuated neuroinflammation

MS

Sun et al. [126]

Deficiency of hexokinase 2 in microglia increases ATP generation through lipid metabolism

AD

Leng et al. [218]

Gangliosides within Aβ aggregates inhibit microglial detection of amyloid plaques by evading a negative immune receptor.

AD

Gonzalez-Gil et al. [219]

ApoE

ApoE pathway, driven by TREM2, switches microglial phenotype from homeostatic to neurodegenerative

ALS and AD

Krasemann et al. [13]

Microglia expressing ApoE4 display inflammatory gene signatures and show reduced uptake and clearance of Aβ

AD

Lin et al. [220]

ApoE3 lipoprotein induces microglial migration towards injected Aβ, facilitates Aβ uptake, and ameliorates detrimental effects of Aβ on cognition

AD

Fitz et al. [60]

ApoE4 downregulates genes involved in mitochondrial OXPHOS and promotes genes required for lipogenesis; The APOE4-driven lipid accumulation impairs microglial surveillance of neuronal network activity

AD

Victor et al. [221]

ApoE3 expression in microglia enhances their accumulation around amyloid plaques and reduces amyloid pathology, while ApoE4 impairs lipid metabolism, compromising or having no effect on these processes

APOE4 human brains showed a reduction in microglia surrounding amyloid plaques and an increased accumulation of lipid droplets

AD

Liu et al. [222]

APOE4 microglia have increased aerobic glycolysis, higher HIF-1α expression, altered lipid metabolism, and exacerbated amyloid plaque-induced microglial activation

AD

Lee et al. [223]

ApoE4 enhances cholesterol synthesis, causing disrupted cholesterol trafficking by sequestering free cholesterol in lysosomes, which hinders microglia’s ability to clear myelin debris

MS

Marschallinger et al. [176]

Iron

Iron-containing microglia in the frontal cortex (near Aβ plaques) and the hippocampus of AD patients

AD

Zeineh et al. [86]

Van Duijn et al. [87]

Enrichment of iron within activated microglia at the rim of chronic active white matter demyelinating lesions

MS

Zrzavy et al. [224]

Mehta et al. [138]

Iron retention within microglia elevates glycolytic activity and enhances TNFα expression.

AD

Holland et al. [88]

IFNγ and Aβ peptides increase glycolytic enzymes, enhance iron retention, and reduce phagocytosis by microglia

in vitro

McIntosh et al. [89]

Coupling of HIF-1α and iron-induced response in a subset of microglia

MS

Proto et al. [140]

Disturbances in iron metabolism are primarily linked to microglia

HD

Simmons et al. [197]

Amino Acids

Upregulation of glutaminase enzymatic activity in microglia

AD, MS, and ALS

Gao et al. [67]

Shijie et al. [225]

Niida et al. [211]

Stimulation of microglia by α-SYN leads to increased extracellular glutamate

PD

Reynolds et al. [173]

A mutant huntingtin fragment can activate the kynurenine pathway in microglia

HD

Giorgini et al. [192]

Repeated administration of methionine enhances microglial activation

AD

Alachkar et al. [76]

Knocking out IL4I1 (the amino acid oxidase) in myeloid cells leads to failure in resolving inflammation associated with microglia, resulting in inefficient remyelination

MS

Hu et al. [135]

Altered levels of aromatic amino acid metabolites in CSF samples of MS patients resulted in an imbalance in the production of immunomodulatory cytokines, particularly affecting a subset of monocytes with a gene signature resembling homeostatic microglia.

MS

Fitzgerald et al. [136]

Hippocampal neuronal death is associated with immunosuppressive CD11c + microglia and extracellular arginase

AD

Kan et al. [81]