Table 5.
Functions and phenotypes of microglia in Alzheimer's disease
| RNA |
Three microglia phenotypes. All express: Hexb and Cst3 ‘Homeostatic’ phenotype: Cx3cr1, P2ry12, Tmem119, Hexb, Cst3, Cx3cr1, Ctsd, Csf1r, Ctss, Sparc, Tmsb4x, P2ry12, P2ry13, C1qa and C1qb TREM-2-independent, ‘intermediate state’ microglia phenotype: ↑ Tyrobp, Apoe, B2m, Ctsd, Ctsb, Fth1 and Lyz2 ↓Cx3cr1, P2ry12, P2ry13 and Tmem119 TREM-2 dependent, damage-associated microglia (DAM) phenotype: ↑↑ Tyrobp, Apoe, B2m, Ctsd, Ctsb, Fth1 and Lyz2 ↑Cst7, Lpl, Trem2, Axl, Cstsl, Cd9, Csf1, Ccl6, Itgax, Clec7a, Lilrb4 and Timp2 ↓↓ Cx3cr1, P2ry12, P2ry13 and Tmem119 (5xFAD at 3 and 8 months, single-cell RNA-seq [179]) |
|
Microglia neurodegenerative phenotype (MGnD) ↓↓ P2ry12, Tmem119, Gpr34, Jun, Olfml3, Csf1r, Hexb, Mertk, Rhob, Cx3cr1, Tgfbr1, Tgfb1, Mef2a, Mafb, Jun, Sall1 and Egr1 (‘homeostatic’ genes) ↑ Spp1, Itgax, Axl, Lilrb4, Clec7a, Ccl2, Csf1 and Apoe (‘inflammatory’ genes) (APP-PS1 at 7, 10 and 17 months. MGnD is also seen in ALS (SOD1G93A mice) and in MS (acute EAE), single-cell RNA-seq [191]) | |
| Protein |
Three microglia phenotypes: Phenotype 1: Clec7a−P2ry12+ (not associated with Aβ plaques) Phenotype 2: Clec7aloP2ry12lo (in close proximity to Aβ plaques) Phenotype 3: Clec7a+P2ry12– Transition from Clec7a− to Clec7aint to Clec7ahi correlated with increased mRNA expression of Apoe and suppression of homeostatic molecules (APP-PS1, immunohistochemistry [191]) |
|
Three FCRLS+CD11b+ microglia phenotypes: Phenotype 1: Clec7a− Phenotype 2: Clec7aint Phenotype 3: Clec7a+ (APP-PS1, flow cytometry [191]) | |
|
Iba-1+CD11c+TIMP2+ microglia Co-localized with Aβ+, Csf1 and Lpl (5xFAD, immunohistochemistry & smFISHa [179]) | |
|
Neuro- protective roles |
Microglia encircle Aβ plaques to prevent further growth and dissemination into the parenchyma [63], reducing damage to local neurites [295] Microglia may contribute to the phagocytic and enzymatic clearance of the Aβ plaque deposits [82] TREM2 expressed by damage-associated microglia is thought to directly recognise Aβ to enhance engulfment and lysosomal degradation of the protein [338, 357, 366] TREM2-dependent microglia functions are required to prevent seeding of plaques earlier in AD, whilst later on enhance the consolidation of Aβ into highly compact plaques [222] |
|
Neuro- toxic roles |
Microglia cause synapse and neuronal damage, injury, or loss, resulting in memory loss and cognitive decline [152, 284, 291, 294–296] Microglia contribute to the formation and growth of Aβ plaques [294, 295] Microglial secretion of tau-laden exosomes help seed and spread tau aggregates throughout the CNS [12, 61] |
aSingle molecule fluorescence in situ hybridization