Microglial activation plays a crucial role in neuroinflammation and neurodegeneration, particularly in conditions like Alzheimer's disease (AD). Ndoja et al. demonstrated that the ubiquitin ligase COP1 regulates the expression of the pro-inflammatory transcription factor c/EBPβ in microglia, suggesting a post-translational mechanism that could be targeted to modulate neuroinflammatory responses (ref: Ndoja doi.org/10.1016/j.cell.2020.07.011/). Liu et al. identified a unique population of glycolytic macrophages/microglia in the retinal angiogenic niche, termed pathological retinal angiogenesis-associated glycolytic macrophages/microglia (PRAGMs), which exhibit both M1 and M2 markers and produce pro-inflammatory cytokines, linking metabolic states to immune responses in retinal diseases (ref: Liu doi.org/10.1126/scitranslmed.aay1371/). Ewers et al. explored the relationship between microglial activation, indicated by cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2), and amyloid-beta accumulation, finding that higher levels of sTREM2 correlate with slower rates of amyloid accumulation, highlighting a potentially protective role of activated microglia in AD (ref: Ewers doi.org/10.15252/emmm.202012308/). Furthermore, Nguyen et al. revealed that genetic risk factors such as APOE and TREM2 influence the population of amyloid-responsive microglia, with risk variants associated with a reduction in these protective cells, indicating a complex interplay between genetics and immune response in AD (ref: Nguyen doi.org/10.1007/s00401-020-02200-3/).

Microglia are increasingly recognized for their roles in neurodegenerative diseases, with studies highlighting their diverse functions and interactions. Kracht et al. provided insights into the development of human fetal microglia, showing that they acquire homeostatic immune-sensing properties early in gestation, which may influence their later roles in neurodegenerative conditions (ref: Kracht doi.org/10.1126/science.aba5906/). In the context of Alzheimer's disease, Nguyen et al. further elucidated how genetic variants in APOE and TREM2 impact microglial responses to amyloid-beta, suggesting that these genetic factors may modulate the neuroinflammatory environment (ref: Nguyen doi.org/10.1007/s00401-020-02200-3/). Agarwal et al. presented a single-cell transcriptomic atlas of the substantia nigra, revealing that unlike in AD, microglial involvement in Parkinson's disease (PD) appears less significant, indicating distinct pathophysiological mechanisms between these neurodegenerative diseases (ref: Agarwal doi.org/10.1038/s41467-020-17876-0/). Additionally, Ruan et al. investigated the therapeutic potential of a P2RX7 inhibitor in tauopathies, demonstrating its ability to suppress disease phenotypes in tau transgenic mice, which may provide a new avenue for treatment in neurodegenerative diseases characterized by tau accumulation (ref: Ruan doi.org/10.1186/s13024-020-00396-2/).

Microglia play essential roles in the development and maintenance of the central nervous system (CNS). Kracht et al. highlighted the heterogeneity of human fetal microglia, which acquire immune-sensing properties during early development, suggesting that these cells are crucial for establishing homeostasis in the CNS (ref: Kracht doi.org/10.1126/science.aba5906/). Nemes-Baran et al. explored the role of microglia in oligodendrogenesis, showing that fractalkine-dependent pruning of oligodendrocyte progenitor cells (OPCs) by microglia regulates myelination during early postnatal development, indicating a critical interaction between these cell types in CNS maturation (ref: Nemes-Baran doi.org/10.1016/j.celrep.2020.108047/). Furthermore, Böttcher et al. utilized single-cell mass cytometry to analyze myeloid cell composition in multiple sclerosis lesions, revealing distinct phenotypic changes in microglia that may influence their roles in homeostasis and disease progression (ref: Böttcher doi.org/10.1186/s40478-020-01010-8/). These findings underscore the multifaceted roles of microglia in both developmental processes and the maintenance of CNS health.

The interactions between microglia and other cell types are pivotal in both health and disease. Liu et al. investigated the metabolic interactions between myeloid cells and endothelial cells in the retinal angiogenic niche, identifying a unique population of glycolytic macrophages/microglia that exhibit an angiogenic phenotype, which may influence vascular pathology (ref: Liu doi.org/10.1126/scitranslmed.aay1371/). Ndoja et al. focused on the regulatory mechanisms of microglial activation, demonstrating that the ubiquitin ligase COP1 suppresses neuroinflammation by degrading c/EBPβ, a transcription factor involved in pro-inflammatory gene expression, thereby highlighting a potential therapeutic target for modulating microglial responses (ref: Ndoja doi.org/10.1016/j.cell.2020.07.011/). Additionally, Nguyen et al. revealed that genetic variants in APOE and TREM2 affect the population of amyloid-responsive microglia, suggesting that these interactions are crucial for understanding the immune landscape in Alzheimer's disease (ref: Nguyen doi.org/10.1007/s00401-020-02200-3/). These studies collectively emphasize the importance of microglial interactions with other cell types in shaping immune responses and influencing disease outcomes.

Research into therapeutic targets for modulating microglial activity has gained momentum, particularly in neurodegenerative diseases. Ruan et al. investigated the effects of a P2RX7 inhibitor on tau transgenic mice, finding that it suppresses exosome secretion and mitigates disease phenotypes, suggesting that targeting P2RX7 could be a promising strategy for tauopathies (ref: Ruan doi.org/10.1186/s13024-020-00396-2/). Ewers et al. explored the relationship between microglial activation, as indicated by CSF levels of sTREM2, and amyloid-beta accumulation in Alzheimer's disease, proposing that enhancing microglial activation could slow disease progression (ref: Ewers doi.org/10.15252/emmm.202012308/). Additionally, Nguyen et al. highlighted the role of genetic factors such as APOE and TREM2 in regulating microglial responses to amyloid-beta, indicating that these pathways could be targeted for therapeutic intervention (ref: Nguyen doi.org/10.1007/s00401-020-02200-3/). These findings underscore the potential for developing therapies that modulate microglial function to improve outcomes in neurodegenerative diseases.