:: infobox .infobox-celltype
Allen Atlas ID: CS202210140_3700
Lineage: Glial > Immune > [Microglia[/entities/[microglia[/entities/[microglia[/entities/[microglia--TEMP--/entities)--FIX--
Markers: CX3CR1, P2RY12, TMEM119, IBA1 (AIF1), CSF1R, [TREM2[/entities/[trem2[/entities/[trem2[/entities/[trem2--TEMP--/entities)--FIX--
Brain Regions: Widespread (all brain regions), Higher density in gray matter
Disease Vulnerability: Alzheimer's Disease, Parkinson's Disease, ALS, Multiple Sclerosis
::
Microglia is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Microglia are the resident immune cells of the central nervous system (CNS), constituting approximately 10-15% of all cells in the brain. As the primary phagocytic cells in the CNS, microglia play critical roles in brain development, homeostasis, immune surveillance, and neurodegeneration. Unlike peripheral macrophages, microglia originate from embryonic yolk sac progenitors and self-renew throughout life without significant contribution from bone marrow-derived cells under normal conditions. Microglia are central players in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), where their dysfunction contributes to disease progression through neuroinflammation, impaired clearance of pathological proteins, and synaptic dysfunction.
Microglia arise from primitive macrophages in the embryonic yolk sac:
Microglia maintain CNS residency through:
In the healthy brain, microglia exhibit:
Microglia adopt diverse activation states:
M1 (Classical Activation)
M2 (Alternative Activation)
Disease-Associated Microglia (DAM)
Neurodegeneration-Associated Microglia (NAM)
Microglia eliminate inappropriate synapses during development:
Microglia are central to AD pathogenesis:
Microglial involvement in PD:
Microglia in ALS:
The study of Microglia has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
ASE-containing genes highly enriched for neuronally expressed genes: putamen FDR p=9.97x10^-235, substantia nigra FDR p=3.05x10^-97. Also significant enrichments for oligodendrocyte, astrocyte, microglia, and endothelial gene sets. Strength of evidence for cellular specificity was striking for ASEs compared to eQTLs.
Model System: Human putamen and substantia nigra
Statistical Significance: Putamen: FDR p=9.97x10^-235; substantia nigra: FDR p=3.05x10^-97
Sebastian Guelfi et al., (2020)
Revealed tumor heterogeneity, tumor microenvironment dynamics, and potential therapeutic strategies for recurrent GBM. Identified neural tri-lineage cancer hierarchy centered around glial progenitor-like cells.
Model System: Human glioblastoma multiforme tissue
Statistical Significance: Not applicable (review)
Awuah Wireko Andrew et al., (2023)
Identified proinflammatory microglia in developing GBMs, abundance of anti-inflammatory macrophages and MDSCs in end-stage tumors. Showed effects of temozolomide and irradiation on immune populations.
Model System: Human GBM tissue
Statistical Significance: Not applicable
Awuah Wireko Andrew et al., (2023)
Revealed role of astrocytes and microglia in unfolded protein response and cytokine signalling. CD4+ CTLs more prevalent with increased interferon-gamma response. Endothelial cells especially sensitive to IFNG.
Model System: Human midbrain specimens from PD patients and healthy individuals
Statistical Significance: Not applicable
Awuah Wireko Andrew et al., (2023)
Identified mixed glia population with GFAP and OLIG2 markers exclusively in TLE. Found higher pro-inflammatory cytokine markers (IL1B) in microglia from drug-refractory epilepsy patients. Discovered potassium channel downregulation via IGSF3-Kir4.1 interaction.
Model System: Human neocortex samples from TLE patients
Statistical Significance: Not applicable
Awuah Wireko Andrew et al., (2023)
Identified vascular endothelial cells involved in angiogenesis, microglia/macrophages modulating endothelial cells via SPP1 and IGF1. Discovered disease-associated microglia (DAM) subtype contributing to hindlimb locomotor recovery. Revealed NSC subpopulations with activation patterns and OPCs with heightened neurogenic capacity post-SCI.
Model System: Murine spinal cord injury models
Statistical Significance: Not applicable
Awuah Wireko Andrew et al., (2023)
Unveiled cellular heterogeneity, distinct brain clusters, microglial subtypes, and trajectory branches of monocytes/macrophages. Astrocytic responses revealed major subtypes, gene expression changes, and metabolic pathways. NK cell numbers and activity increased; CD14+ monocytes decreased post-stroke.
Model System: Mouse model of ischemic stroke, aged mouse brain
Statistical Significance: Not applicable
Awuah Wireko Andrew et al., (2023)
Microglia expressed highest TLR5 levels; adult microglia expressed higher TLR5 than neonatal microglia; astrocytes and Oli-neu cells expressed low TLR5; TLR5 was barely detectable in cortical neurons
Model System: Primary neonatal microglia, adult microglia, astrocytes, and cortical neurons from C57BL/6 mice; Oli-neu oligodendroglial precursor cell line
Statistical Significance: P<0.05; P<0.01
TLR5 protein readily detectable in microglia and astrocytes (to lesser extent); not detected in cortical neurons; antibody specificity confirmed in Tlr5-/- mice
Model System: Cultured neonatal microglia, astrocytes, and neurons from C57BL/6 (WT) and Tlr5-/- mice
TNF-alpha, RANTES, MIP-2, IL-10, IL-6, and GRO-alpha significantly released from WT microglia in response to 100ng/ml flagellin; IL-1beta not detected; Tlr5-/- microglia failed to respond to flagellin; LPS induced enhanced MIP-2 response in Tlr5-/- vs WT microglia
Model System: Cultured neonatal microglia from C57BL/6 (WT) and Tlr5-/- mice
Statistical Significance: P<0.05; P<0.01 vs control
Flagellin did not induce NO production in microglia; LPS served as positive control
Model System: Cultured neonatal WT microglia
Statistical Significance: P<0.01 vs control; n.s. for FLA vs control
Flagellin induced neuronal loss in dose and time-dependent manner; 10ng/ml caused 19.2% loss (P=0.017); 100ng/ml caused 30.9% loss (P=0.0042) after 72h; neurons co-cultured with Tlr5-/- microglia protected; flagellin did not affect neurons in absence of microglia
Model System: Co-cultures of cortical neurons and microglia from WT or Tlr5-/- mice (ratio 8:1)
Statistical Significance: P<0.05; P<0.01 vs control
Flagellin induced significant neuronal loss of 32.3% in cerebral cortex; active caspase-3 positive cells increased by 58.0%; microglial numbers increased by 52.3%
Model System: C57BL/6 mice (6-8 weeks old male)
Statistical Significance: P<0.05
Cytokine induction in Tlr2/4-/- microglia similar to WT after flagellin exposure, excluding LPS or TLR2 ligand contamination in recombinant flagellin
Model System: Tlr2/4-/- microglia
Statistical Significance: Data not shown
No cellular injury or loss observed even at 5 ug/ml flagellin; cytokine reduction at 1000ng/ml not due to toxicity
Model System: Cultured C57BL/6 microglia
Statistical Significance: n.s.
Thousands of regulatory sequences display disease-associated chromatin changes. Over 70% of transcriptional variance explained by chromatin accessibility. Disease progression associated with epigenome erosion marked by global shifts in chromatin accessibility and loss of cell identity. Microglial enhancers are hotspots for AD GWAS hits.
Model System: Human postmortem AD and control brains
Statistical Significance: Not specified
Cláudio Gouveia Roque et al., (2024)
In astrocytes, APOE most strongly correlated with CLU (AD genetic risk factor) and CST3. In microglia, APOE co-expressed with immune-related genes TREM2, TYROBP, C1QA/B/C. ITM2B (inhibitor of amyloid-beta aggregation) co-expressed in both cell types. Pathway enrichment: antigen processing/presentation, complement system in microglia; protein processing in ER, antigen processing in astrocytes. Isoform-specific patterns showed differences in microglia but not astrocytes - strong co-expression in APOE e2e3 with CST3 and complement genes but not TREM2.
Model System: Human frontal cortex from ROSMAP - two snRNA-seq datasets
Statistical Significance: FDR p < 0.05 for pathway enrichment; top 200 genes used for astrocyte analysis due to too many significant genes
85-90% of most predictive molecular pathways in brain were also top predictors in blood. Common pathways: blood coagulation, angiogenesis, p53, B cell activation, Wnt signaling. Brain cell types: astrocytes (38% ROSMAP, 22% HBTRC), microglia (4% ROSMAP, 48% HBTRC), oligodendrocyte precursor cells (35% ROSMAP, 17% HBTRC), neurons, endothelial cells.
Model System: ROSMAP and HBTRC brain tissues, ADNI blood
Statistical Significance: Not applicable (enrichment analysis)
Aβ molecular associates enriched in pyramidal cells (q=0.002, δ=3.804) and endothelial-mural cells (q=0.008, δ=2.950); tau associates enriched in interneurons (q=0.021, δ=2.834); Aβ∙tau signature highly enriched in microglia (q<0.001, δ=10.425)
Model System: Gene sets from transcriptomic analysis with single-cell data from mouse somatosensory cortex and hippocampus CA1
Statistical Significance: q < 0.05
Sanchez-Rodriguez et al., (2023)
Excitatory neurons had most eGenes (7,331), followed by inhibitory neurons (2,214), oligodendrocytes (1,968), astrocytes (1,705), OPCs (1,284), microglia (899), and endothelial cells (532). 46% of eGenes (4,598) were cell type-specific.
Model System: Human DLPFC - seven cell types: excitatory neurons, inhibitory neurons, astrocytes, microglia, oligodendrocytes, OPCs, endothelial cells
Statistical Significance: FDR < 0.05
1,258 unique eGenes detected only in excitatory neuron subtypes but not in pooled cell type analysis. Subtype analysis enhanced eGene discovery across all cell types including astrocytes, microglia, oligodendrocytes and OPCs.
Model System: Human DLPFC - 64 cell subtypes across 7 major cell types
Statistical Significance: FDR < 0.05
rs2288911 is a microglia-specific eQTL for APOE expression (P=1.1x10^-13). Associated with cerebral amyloid angiopathy (CAA) (P=1.18x10^-7) but not AD pathology or amyloid/tau proteinopathy. Association with CAA persists after adjusting for APOE4 (P=9.9x10^-6). No interaction with APOE4 on CAA.
Model System: Human DLPFC microglia from ROS/MAP participants
Statistical Significance: P=1.1x10^-13 for eQTL; P=1.18x10^-7 for CAA association
eSNPs enriched within 100kb of TSS, in euchromatin and enhancers. Microglial eSNPs enriched in microglial enhancer regions. APOE rs2288911 is 40.2kb from APOE in a microglial-specific enhancer region marked by H3K27ac and H3K4me3, with PLAC-seq showing physical proximity to APOE gene.
Model System: Human DLPFC tissue and brain cell types
Statistical Significance: Fisher's exact test for enrichment
21 eGenes colocalized with 20 AD loci. BIN1 risk haplotype (rs4663105) drives expression only in microglia. Four new colocalizations: AC004797.1, AL596218.1, AP001439.1, ITGA2B. Microglia harbored most implicated target genes. Cell type-level analysis improved over bulk (8 colocalized) and subtype-level (11 colocalized).
Model System: Human DLPFC cell types
Statistical Significance: PP.H4 > 0.8 for colocalization
Large excess of microglial genes involved in AD. TWAS identified 24 microglial genes not previously associated with AD (including FNIP2 and RAPGEF2). All nine microglial colocalized effects in AD also found in TWAS. Oligodendroglial genes implicated in PD.
Model System: Human DLPFC - all cell types
Statistical Significance: FDR <= 0.05
Microglia play dual roles in AD: protective functions (Aβ clearance, plaque corralling) via TREM2 signaling, and harmful functions (synapse engulfment via complement, inflammatory cytokine release). GWAS identified >20 AD risk genes highly expressed in microglia. TREM2 loss-of-function mutations increase AD risk ~3-fold. DAM (disease-associated microglia) transcriptional state identified in mouse models.
Model System: Literature review
Statistical Significance: N/A - review paper
LC lesioning leads to increased microglial and astrocytic activation; increased iNOS expression; LC-lesioned animals show enhanced proinflammatory response to Aβ deposition; impaired recruitment of microglia to Aβ plaque sites and diminished phagocytosis capabilities
Model System: APP/PS1 mice, P301S tau mice, control rats with LC lesions
Statistical Significance: Not reported
ASE-containing genes highly enriched for neuronally expressed genes: putamen FDR p=9.97x10^-235, substantia nigra FDR p=3.05x10^-97. Also significant enrichments for oligodendrocyte, astrocyte, microglia, and endothelial gene sets. Strength of evidence for cellular specificity was striking for ASEs compared to eQTLs.
Model System: Human putamen and substantia nigra
Statistical Significance: Putamen: FDR p=9.97x10^-235; substantia nigra: FDR p=3.05x10^-97
Sebastian Guelfi et al., (2020)
Revealed tumor heterogeneity, tumor microenvironment dynamics, and potential therapeutic strategies for recurrent GBM. Identified neural tri-lineage cancer hierarchy centered around glial progenitor-like cells.
Model System: Human glioblastoma multiforme tissue
Statistical Significance: Not applicable (review)
Awuah Wireko Andrew et al., (2023)
Identified proinflammatory microglia in developing GBMs, abundance of anti-inflammatory macrophages and MDSCs in end-stage tumors. Showed effects of temozolomide and irradiation on immune populations.
Model System: Human GBM tissue
Statistical Significance: Not applicable
Awuah Wireko Andrew et al., (2023)
Revealed role of astrocytes and microglia in unfolded protein response and cytokine signalling. CD4+ CTLs more prevalent with increased interferon-gamma response. Endothelial cells especially sensitive to IFNG.
Model System: Human midbrain specimens from PD patients and healthy individuals
Statistical Significance: Not applicable
Awuah Wireko Andrew et al., (2023)
Identified mixed glia population with GFAP and OLIG2 markers exclusively in TLE. Found higher pro-inflammatory cytokine markers (IL1B) in microglia from drug-refractory epilepsy patients. Discovered potassium channel downregulation via IGSF3-Kir4.1 interaction.
Model System: Human neocortex samples from TLE patients
Statistical Significance: Not applicable
Awuah Wireko Andrew et al., (2023)
Identified vascular endothelial cells involved in angiogenesis, microglia/macrophages modulating endothelial cells via SPP1 and IGF1. Discovered disease-associated microglia (DAM) subtype contributing to hindlimb locomotor recovery. Revealed NSC subpopulations with activation patterns and OPCs with heightened neurogenic capacity post-SCI.
Model System: Murine spinal cord injury models
Statistical Significance: Not applicable
Awuah Wireko Andrew et al., (2023)
Unveiled cellular heterogeneity, distinct brain clusters, microglial subtypes, and trajectory branches of monocytes/macrophages. Astrocytic responses revealed major subtypes, gene expression changes, and metabolic pathways. NK cell numbers and activity increased; CD14+ monocytes decreased post-stroke.
Model System: Mouse model of ischemic stroke, aged mouse brain
Statistical Significance: Not applicable
Awuah Wireko Andrew et al., (2023)
Microglia expressed highest TLR5 levels; adult microglia expressed higher TLR5 than neonatal microglia; astrocytes and Oli-neu cells expressed low TLR5; TLR5 was barely detectable in cortical neurons
Model System: Primary neonatal microglia, adult microglia, astrocytes, and cortical neurons from C57BL/6 mice; Oli-neu oligodendroglial precursor cell line
Statistical Significance: P<0.05; P<0.01
TLR5 protein readily detectable in microglia and astrocytes (to lesser extent); not detected in cortical neurons; antibody specificity confirmed in Tlr5-/- mice
Model System: Cultured neonatal microglia, astrocytes, and neurons from C57BL/6 (WT) and Tlr5-/- mice
TNF-alpha, RANTES, MIP-2, IL-10, IL-6, and GRO-alpha significantly released from WT microglia in response to 100ng/ml flagellin; IL-1beta not detected; Tlr5-/- microglia failed to respond to flagellin; LPS induced enhanced MIP-2 response in Tlr5-/- vs WT microglia
Model System: Cultured neonatal microglia from C57BL/6 (WT) and Tlr5-/- mice
Statistical Significance: P<0.05; P<0.01 vs control
Flagellin did not induce NO production in microglia; LPS served as positive control
Model System: Cultured neonatal WT microglia
Statistical Significance: P<0.01 vs control; n.s. for FLA vs control
Flagellin induced neuronal loss in dose and time-dependent manner; 10ng/ml caused 19.2% loss (P=0.017); 100ng/ml caused 30.9% loss (P=0.0042) after 72h; neurons co-cultured with Tlr5-/- microglia protected; flagellin did not affect neurons in absence of microglia
Model System: Co-cultures of cortical neurons and microglia from WT or Tlr5-/- mice (ratio 8:1)
Statistical Significance: P<0.05; P<0.01 vs control
Flagellin induced significant neuronal loss of 32.3% in cerebral cortex; active caspase-3 positive cells increased by 58.0%; microglial numbers increased by 52.3%
Model System: C57BL/6 mice (6-8 weeks old male)
Statistical Significance: P<0.05
Cytokine induction in Tlr2/4-/- microglia similar to WT after flagellin exposure, excluding LPS or TLR2 ligand contamination in recombinant flagellin
Model System: Tlr2/4-/- microglia
Statistical Significance: Data not shown
No cellular injury or loss observed even at 5 ug/ml flagellin; cytokine reduction at 1000ng/ml not due to toxicity
Model System: Cultured C57BL/6 microglia
Statistical Significance: n.s.
Thousands of regulatory sequences display disease-associated chromatin changes. Over 70% of transcriptional variance explained by chromatin accessibility. Disease progression associated with epigenome erosion marked by global shifts in chromatin accessibility and loss of cell identity. Microglial enhancers are hotspots for AD GWAS hits.
Model System: Human postmortem AD and control brains
Statistical Significance: Not specified
Cláudio Gouveia Roque et al., (2024)
In astrocytes, APOE most strongly correlated with CLU (AD genetic risk factor) and CST3. In microglia, APOE co-expressed with immune-related genes TREM2, TYROBP, C1QA/B/C. ITM2B (inhibitor of amyloid-beta aggregation) co-expressed in both cell types. Pathway enrichment: antigen processing/presentation, complement system in microglia; protein processing in ER, antigen processing in astrocytes. Isoform-specific patterns showed differences in microglia but not astrocytes - strong co-expression in APOE e2e3 with CST3 and complement genes but not TREM2.
Model System: Human frontal cortex from ROSMAP - two snRNA-seq datasets
Statistical Significance: FDR p < 0.05 for pathway enrichment; top 200 genes used for astrocyte analysis due to too many significant genes
85-90% of most predictive molecular pathways in brain were also top predictors in blood. Common pathways: blood coagulation, angiogenesis, p53, B cell activation, Wnt signaling. Brain cell types: astrocytes (38% ROSMAP, 22% HBTRC), microglia (4% ROSMAP, 48% HBTRC), oligodendrocyte precursor cells (35% ROSMAP, 17% HBTRC), neurons, endothelial cells.
Model System: ROSMAP and HBTRC brain tissues, ADNI blood
Statistical Significance: Not applicable (enrichment analysis)
Aβ molecular associates enriched in pyramidal cells (q=0.002, δ=3.804) and endothelial-mural cells (q=0.008, δ=2.950); tau associates enriched in interneurons (q=0.021, δ=2.834); Aβ∙tau signature highly enriched in microglia (q<0.001, δ=10.425)
Model System: Gene sets from transcriptomic analysis with single-cell data from mouse somatosensory cortex and hippocampus CA1
Statistical Significance: q < 0.05
Sanchez-Rodriguez et al., (2023)
Excitatory neurons had most eGenes (7,331), followed by inhibitory neurons (2,214), oligodendrocytes (1,968), astrocytes (1,705), OPCs (1,284), microglia (899), and endothelial cells (532). 46% of eGenes (4,598) were cell type-specific.
Model System: Human DLPFC - seven cell types: excitatory neurons, inhibitory neurons, astrocytes, microglia, oligodendrocytes, OPCs, endothelial cells
Statistical Significance: FDR < 0.05
1,258 unique eGenes detected only in excitatory neuron subtypes but not in pooled cell type analysis. Subtype analysis enhanced eGene discovery across all cell types including astrocytes, microglia, oligodendrocytes and OPCs.
Model System: Human DLPFC - 64 cell subtypes across 7 major cell types
Statistical Significance: FDR < 0.05
rs2288911 is a microglia-specific eQTL for APOE expression (P=1.1x10^-13). Associated with cerebral amyloid angiopathy (CAA) (P=1.18x10^-7) but not AD pathology or amyloid/tau proteinopathy. Association with CAA persists after adjusting for APOE4 (P=9.9x10^-6). No interaction with APOE4 on CAA.
Model System: Human DLPFC microglia from ROS/MAP participants
Statistical Significance: P=1.1x10^-13 for eQTL; P=1.18x10^-7 for CAA association
eSNPs enriched within 100kb of TSS, in euchromatin and enhancers. Microglial eSNPs enriched in microglial enhancer regions. APOE rs2288911 is 40.2kb from APOE in a microglial-specific enhancer region marked by H3K27ac and H3K4me3, with PLAC-seq showing physical proximity to APOE gene.
Model System: Human DLPFC tissue and brain cell types
Statistical Significance: Fisher's exact test for enrichment
21 eGenes colocalized with 20 AD loci. BIN1 risk haplotype (rs4663105) drives expression only in microglia. Four new colocalizations: AC004797.1, AL596218.1, AP001439.1, ITGA2B. Microglia harbored most implicated target genes. Cell type-level analysis improved over bulk (8 colocalized) and subtype-level (11 colocalized).
Model System: Human DLPFC cell types
Statistical Significance: PP.H4 > 0.8 for colocalization
Large excess of microglial genes involved in AD. TWAS identified 24 microglial genes not previously associated with AD (including FNIP2 and RAPGEF2). All nine microglial colocalized effects in AD also found in TWAS. Oligodendroglial genes implicated in PD.
Model System: Human DLPFC - all cell types
Statistical Significance: FDR <= 0.05
Microglia play dual roles in AD: protective functions (Aβ clearance, plaque corralling) via TREM2 signaling, and harmful functions (synapse engulfment via complement, inflammatory cytokine release). GWAS identified >20 AD risk genes highly expressed in microglia. TREM2 loss-of-function mutations increase AD risk ~3-fold. DAM (disease-associated microglia) transcriptional state identified in mouse models.
Model System: Literature review
Statistical Significance: N/A - review paper
LC lesioning leads to increased microglial and astrocytic activation; increased iNOS expression; LC-lesioned animals show enhanced proinflammatory response to Aβ deposition; impaired recruitment of microglia to Aβ plaque sites and diminished phagocytosis capabilities
Model System: APP/PS1 mice, P301S tau mice, control rats with LC lesions
Statistical Significance: Not reported
Ginhoux F, Greter M, Leboeuf M, et al. "Fate mapping analysis reveals that adult microglia derive from primitive macrophages." Science (2010). PMID:20937814
Wolf SA, Boddeke HW, Kettenmann H. "Microglia in physiology and disease." Annual Review of Physiology (2017). PMID:27959619
Salter MW, Stevens B. "Microglia emerge as central players in brain disease." Nature Medicine (2017). PMID:28886007
Zhou Y, Song WM, Andhey PS, et al. "Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer's disease." Nature Medicine (2020). PMID:32047258
Hansen DV, Hanson JE, Sheng M. "Microglia in Alzheimer's disease." Journal of Cell Biology (2018). PMID:29378997
Colonna M, Butovsky O. "Microglia function in the central nervous system." Annual Review of Immunology (2017). PMID:28226226
Keren-Shaul H, Spinrad A, Weiner A, et al. "A unique microglia type associated with restricting development of Alzheimer's disease." Cell (2017). PMID:28602351
Prinz M, Jung S, Priller J. "Microglia biology: one century of evolving concepts." Cell (2019). PMID:31787378