Table 2 Features of Newly-described microglial phenotypes
From: Different phenotypes of microglia in animal models of Alzheimer disease
Distinctive Features | unique phenotypic properties | phenotypic markers | Function | Incentives | Formation | Content | Distribution | Immunoreactivity | Animal models | |
|---|---|---|---|---|---|---|---|---|---|---|
Typical microglia | The resident non-activated microglia present ramified morphology with long extension; however, upon activation, they retract the extensions and become amoeboid [18] | -- | TMEM119, CD11B, and P2RY12/P2RY13 expression, with low CD45 expression [78] | Regulate synaptic plasticity, learning, and memory mechanisms [79] | No mention | Erythromyeloid progenitor cells in the embryonic yolk sac [80], with the same origin as that of peripheral macrophages (myeloid progenitors) | Comprise 5–10% of all CNS cells [81] | in all brain regions, mainly in the gray matter [82] | High immunoreactivity for homeostatic markers (GFP in CX3CR1-GFP mice, P2RY12, IBA1, etc.) | --- |
LDAM | Containing large inclusions, i.e., lipofuscin granules [83] | Exhibit a unique transcriptional signature, show phagocytosis deficits, and produce increased levels of ROS and pro-inflammatory cytokines [51] | GRN, solute carrier family 33 Member 1 (SLC33A), SNX17, vacuolar protein sorting retromer complex component (VPS35), NPC2, and CLN3 [54] | Represent a dysfunctional and pro-inflammatory microglia state in the aging brain [51] | Increased extracellular lipid levels, inflammatory events, increased ROS levels, and intracellular metabolic changes [84] | Age-related neuroinflammation [51] | Approximately 50% of microglia in the aging brain accumulate lipid droplets [51] | Frequently found in the hippocampus and thalamus [51] | Immunoreactive for Iba1, Plin2, Plin3 | Five human familial AD mutations (5XFAD) [85] |
DAM | Rounded enlarged bodies, with 45% of DAMs being dystrophic [86] | upregulated expression of genes related to lipid metabolism, phagocytosis, and AD pathology, downregulated expression of homeostatic markers, without changes in expression of inflammatory cytokines [67] | anti-inflammatory DAM genes (e.g., Kcnj2, Nceh1, Timp2, CXCR4), pro-inflammatory DAM-specific gene (e.g.: Ptgs2/Cox2 or Tlr2, CD14, CD44) | Compared with normal microglia, DAMs show progressively increased lipid metabolism and expression of phagocytic genes, and therefore protect against AD and clear Aβ [67] | Accumulation of danger molecules present on apoptotic bodies of dying neural cells, lipid degradation products, and myelin debris [87] | Dependent on TREM2 signaling [67], also partially by APOE | A proportion of DAM increases with aging, accounting for 3% of all microglial cells in 20-month-old mice [67]. | Within the cortex, but not the cerebellum, of AD mice [40] | Immunoreactive for IBA1 and HLA-DR | PS19 tau transgenic, SOD1-G93A transgenic, and aged mice; five human familial AD mutations (5XFAD) and CK-p25; PS2APP and APP/PS1 [67, 88] |
MGnD | A phagocytic microglia phenotype with reduced ramifications and cell volume [89] | The signature genes associated with MGnD regulate lipid metabolism and phagocytosis [54] | Strong downregulated expression of homeostatic genes, with upregulated expression of selective genes including Spp1, Itgax, Axl, Clec7a, Lgals3, Apoe, and Grn [59] | Protective and represent an initial response to neuronal injury | Induced by neuronal apoptosis or Aβ plaques [59] | The switch from homeostatic microglia to MGnD is regulated by the TREM2-APOE pathway [59] | No mention | In APP-PS1 mice, MGnD primarily encircled amyloid plaques and dystrophic neurites, which are blanketed by homeostatic microglia in the periphery. | Low or no immunoreactivity for P2RY12 | |
Dark microglia | Electron microscopy reveals condensed cytoplasm and nucleoplasm, increased projections to synapses, and increased encircling of axon terminals and dendritic spines [90] | a downregulated expression of homeostatic markers, CX3CR1, IBA1 and P2RY12, but strongly expressed the microglia-specific 4D4 in their processes [62] | Strongly express CD11b, Trem246, and 4D4, with downregulated expression of IBA1, CX3CR1, and P2RY12 [64] | Extensively engulfing dendritic spines, axon terminals, and entire synapses | Chronic stress, aging, fractalkine signaling deficiency (CX3 CR1 knockout mice), and Alzheimer’s disease pathology (APP-PS1 mice) [64] | Derived from yolk sac, brain progenitors, or bone marrow-derived cells recruited to the brain in a CCR2‐independent manner [91] | In age-matched APP/PS1 littermates, the number of dark microglia corresponded to almost two‐thirds of the typical microglial population [64] | The hippocampal CA1 region (strata lacunosum-molecular and radiatum), subgranular layers of the cerebral cortex, basolateral nucleus of the amygdala, and hypothalamic median eminence [64] | Low immunoreactivity for homeostatic markers (GFP in CX3CR1-GFP mice, IBA1, CD11b, 4D4, TREM2); no ALDH1L1, OLIG2, P2RY12, 4C12, MHCII, CD206, CD11c expression [64] | |
PAM | Compared with typical microglia, PAM are amoeboid with thicker primary branches and larger cell bodies [93] | enrich many metabolic genes including almost the entire molecular machineries for oxidative phosphorylation, glycolysis and beta oxidation | Characterized by expression of numerous trophic factors including Igf1, Spp1, Lgals1, and Lgals3 [63]; contrastingly, many genes (Apoe, Igf1, Lilrb4, Lyz2, Colec12, Msr1, Map1lc3b) have upregulated expression [94] | Phagocytose newly formed oligodendrocytes and possibly new-born astrocytes during development | No mention | Independent of the TREM2-APOE axis [65] | Comprise one-third of the normal microglial population in APP-PS1 mice [64] | Developing cerebellar white matter and corpus callosum | Immunoreactive for CLEC7A | Trem2−/− or Apoe−/− [65] |
WAM | Cluster in nodules | upregulated genes linked to atherosclerosis, cytokine signaling, and apoptosis [68], downregulation of genes expressed in homeostatic microglia, such as checkpoint genes | Increased expression of the NF-κB pathway and adhesion family GPCR GPR56 (ADGRG1) [95] | May represent a potentially protective response [68] | Aging and cerebral hypoperfusion | Dependent on age and TREM2 but not APOE signaling [68]; APOE dependent [96] | ~ 20% in 21-month-old AD model mice | White matter tracts from the corpus callosum [68] | Immunoreactive for CD68 [96] | MTX rats (MTX through intraperitoneal injection every week at a dose of 200 mg/kg/week for a total of 4 weeks, and a final dose of 800 mg/kg) (97); Apoe−/− mice; APP/PS1 mouse model [68, 98] |
No mention | MHC-II presentation (Cd74, Ctsb, Cstd), inflammatory processes (Cst7, Clec7a, Itgax) putative tissue repair genes (Dkk 1, Spp1, Gpnmb) and AD risk genes like APOE | Increased expression of histocompatibility complex class II genes (Cd74, H2-Ab1, and H2-Aa) and pro-inflammatory genes Cst7, Clec7a, and Itgax (encoding CD11c) | No mention | No mention | No mention | Increased from approximately ~ 3% in 3-month-old mice to ~ 12% of the total microglia in 21-month-old mice | No mention | No mention | ||
IRM | Adopts a reactive morphology after rIFN-β exposure, with reduced dendrite length, branch, and terminal points [99] | the expression of thousands of interferon-stimulated genes [100] | Increased expression of Ifit3, Ifitm3, Irf7, and Oasl2 [100] | Contributing to the inflammatory tone of the aged and AD brain [71] | Aging, viral infection, cuprizone-induced demyelination | can be triggered by nucleic acid (NA)-containing plaques | 15% of all APP/PS1 microglia [97] | No mention | Immunoreactive for IBA1 | 5XFAD mice [96], CK-p25 mice [75], APP-PS1, tauopathy (P301S和P301L) |
NM | Chromosome fragmentation, membrane blebbing, and cell volume shrinkage | Release various pro-inflammatory cytokines and chemokines [101], including tumor necrosis factor-α and chemokine (C-C motif) ligand 2 | -- | Highly pro-inflammatory and immunogenic [72] | Different cellular stimuli, including TNF-α, FAS ligand, TRAIL, IFNγ, ischemia-reperfusion injury, and double-stranded RNA (dsRNA) | Through TLR4 activation | No mention | No mention | Immunoreactive for IBA1 | |
Dystrophic microglia | Characterized by a dystrophic morphology, including process deramification, shortening, gnarling and beading, spheroid formation, and cytoplasmic fragmentation [77], 102] | Significant changes in genes controlling inflammation, including the NF-κB signaling pathway, and upregulation of complement genes C3 and complement factor B | -- | Impaired neuronal activity, iron storage, reduced phagocytosis, and increased ROS production | Aging, iron-fed [76] | Through iron accumulation | There was an increase in the proportion of dystrophic microglia with age. In the case of neurodegenerative pathology, approximately 45% of the microglia were found to be dystrophic. | Near sites of tau pathology and amyloid plaques, in the neocortical gray matter of layers II–III in aged chimpanzees [30, 103] | Immunoreactive for IBA1（104） | aged Tupaia belangeri (mean age 7.5 years), Binge Alcohol Model [104],aged marmosets [105], LPS (0.33 mg/kg) administration to adult rats [106] |