Table 1.
Current evidence of phagocytosis alterations resulting from variants in disease-associated genes expressed in microglia.
| Gene | Associated diseases | Models | Alterations to phagocytosis | References |
|---|---|---|---|---|
| TREM2 | Alzheimer's disease (48, 49) Frontotemporal dementia (50) Parkinson's disease (50) Nasu-Hakola disease (51) | Primary microglia from TREM2−/− mice | Decreased phagocytosis of Aβ relative to WT microglia | (52) |
| Reduced uptake of Aβ-lipoprotein complexes compared with WT and TREM2+/− | (53) | |||
| Reduced uptake of E. coli particles compared with WT controls | (54) | |||
| Human monocyte-derived macrophages from heterozygous carriers of the TREM2 R62H AD-associated variant | Reduced uptake of Aβ-lipoprotein complexes compared with non-carriers | (53) | ||
| shRNA knockdown of TREM2 expression in primary mouse microglia | Reduced uptake of apoptotic neuronal membranes vs. control shRNA treated cells | (36) | ||
| Immunohistochemical analysis of 5XFAD/TREM2−/− mice | Decreased levels of Aβ within microglial phagosomes vs. WT. Haplodeficient TREM2+/− mice showed no significant reductions in Aβ uptake | (55, 56) | ||
| Increased Aβ load in hippocampus of TREM2 knockout mice | (52) | |||
| Immunohistochemical analysis of APPPS1-21/TREM2−/− mice | Decreased Aβ load in hippocampus of TREM2 knockout mice vs. WT at 2 months | (57) | ||
| Decreased Aβ load in hippocampus of TREM2 knockout mice vs. WT at 4 months | (58) | |||
| Increased Aβ load in hippocampus of TREM2 knockout mice vs. WT at 8 months | ||||
| Immunohistochemical analysis of APPPS1-21/TREM2+/− mice | No difference in Aβ plaque load between WT and TREM2+/− mice at 3 or 7 months old | (59) | ||
| iPSC-derived microglia-like cells from carriers of TREM2 T66M and W50C variants | Decreased uptake of apoptotic neurons by TREM2 variant cells than by controls | (60) | ||
| Non-phagocytic CHO cells transfected with TREM2 | TREM2-CHO cells were capable of phagocytosing apoptotic neuronal cells | (61) | ||
| CD33 | Alzheimer's disease (62, 63) | Primary microglia from CD33−/− mice | Increased uptake of Aβ compared with WT microglia | (64) |
| CD33 overexpression in BV2 mouse microglial cell line | Decreased uptake of Aβ compared with control BV2 cells | (64) | ||
| Frontal cortex samples from carriers of protective minor allele SNP rs3865444 | Decreased formic acid-soluble Aβ42 levels in carriers of rs3865444 minor (T) allele than in major allele carriers | (64) | ||
| TM2D3 | Alzheimer's disease (65) | CRISPR-Cas9 knockout in primary human macrophages and U937 human myeloid cell line | Decreased uptake of Aβ and synaptosomes compared with WT | (66) |
| PU.1 | Alzheimer's disease (67) | siRNA knockdown of PU.1 in adult human microglia | Reduced phagocytosis of Aβ compared with controls | (68) |
| α-Synuclein | Parkinson's disease (69) | Human iPSC-derived macrophages from PD patients carrying SNCA triplication mutations | Increased release of α-synuclein and reduced phagocytosis capability compared with controls | (70) |
| Progranulin | Frontotemporal dementia (71, 72), Alzheimer's disease (73, 74) | Microglia specific progranulin knockout in AD mice (Grnflox/flox/PDAPPSw, Ind J20) | Decreased microglial phagocytosis of fluorescent beads in acute brain slices and increased hippocampal Aβ plaque-load vs. WT progranulin AD mice | (75) |
| DAP12 | Nasu-Hakola disease (51) | Primary mouse microglia transfected with mutant DAP12 (lack ITAM signaling motif) | Mutant DAP12 microglia phagocytosed less apoptotic neuronal material than control cells | (36) |
| Bone marrow-derived macrophages from DAP12−/− mice | Reduced phagocytosis of bacteria | (76) | ||
| LRRK2 | Parkinson's disease (77, 78) | Microglia and BMDMs from Lrrk2−/− mice | Reduced uptake of latex beads and E. coli bioparticles by primary microglia and BMDMs from knockout mice vs. WT. | (79) |
| Decreased uptake of beads after injection into midbrain in Lrrk2−/− mice compared with controls | ||||
| MerTK | Multiple sclerosis (80, 81) | in vitro human microglia and macrophages | Pharmacological blockade of MerTK inhibits myelin phagocytosis in vitro | (82) |
| MS patient macrophages display reduced expression of MerTK | (83) |