Recent studies have elucidated the complex roles of microglia in neuroinflammation and neurodegenerative diseases. Brioschi et al. developed a novel Cre-deleter line targeting embryonic brain macrophages, allowing for the differentiation between microglia and border-associated macrophages (BAMs) in the mouse cortex. This genetic tool, driven by the Crybb1 gene, demonstrated nearly complete recombination in embryonic brain macrophages, providing insights into their distinct features and functions (ref: Brioschi doi.org/10.1016/j.immuni.2023.01.028/). In the context of Gaucher disease, Shimizu et al. discovered that the accumulation of β-glucosylceramide activates microglia through Mincle, leading to the phagocytosis of living neurons, which exacerbates the disease symptoms (ref: Shimizu doi.org/10.1016/j.immuni.2023.01.008/). Furthermore, De Schepper et al. highlighted the role of SPP1 in mediating microglial phagocytic states and synaptic engulfment in Alzheimer's disease models, suggesting that SPP1 is crucial for the crosstalk between perivascular cells and microglia (ref: De Schepper doi.org/10.1038/s41593-023-01257-z/). These findings collectively underscore the importance of microglial activation in various neuroinflammatory contexts and their potential as therapeutic targets.

Microglia have emerged as key players in the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease (AD). Zeng et al. introduced STARmap PLUS, a method combining spatial transcriptomics with protein detection, which allows for a comprehensive understanding of cellular dynamics in AD pathology (ref: Zeng doi.org/10.1038/s41593-022-01251-x/). The TREM2 H157Y mutation was shown by Qiao et al. to enhance soluble TREM2 production and facilitate amyloid-β clearance, thereby reducing amyloid pathology and associated neuroinflammation (ref: Qiao doi.org/10.1186/s13024-023-00599-3/). Additionally, Hata et al. reported that early-life infections can reprogram retinal microglia, aggravating age-related macular degeneration, indicating that environmental factors play a significant role in neurodegenerative disease progression (ref: Hata doi.org/10.1172/JCI159757/). These studies illustrate the multifaceted roles of microglia in neurodegenerative diseases, emphasizing their potential as therapeutic targets.

The functional role of microglia in synaptic plasticity is increasingly recognized, particularly in the context of neurodegenerative diseases. De Schepper et al. demonstrated that SPP1 mediates microglial phagocytic activity, which is essential for maintaining synaptic integrity in Alzheimer's disease models (ref: De Schepper doi.org/10.1038/s41593-023-01257-z/). Zhao et al. introduced a multivalent nanobody conjugate that targets both Aβ aggregation and oxidative stress, showcasing a novel approach to mitigate amyloidogenesis and enhance synaptic function (ref: Zhao doi.org/10.1002/adma.202210879/). Furthermore, Rosito et al. revealed that microglial activation leads to significant microtubule remodeling, suggesting that cytoskeletal dynamics are crucial for microglial function during synaptic plasticity (ref: Rosito doi.org/10.1016/j.celrep.2023.112104/). These findings collectively highlight the intricate relationship between microglial activity and synaptic health, suggesting that targeting microglial functions may offer therapeutic avenues for neurodegenerative diseases.

Microglia play a pivotal role in the immune response within the central nervous system, influencing both neuroinflammation and neurodegeneration. Brioschi et al. developed a Cre-deleter line that allows for the specific targeting of embryonic-derived brain macrophages, revealing distinct features of microglia and BAMs (ref: Brioschi doi.org/10.1016/j.immuni.2023.01.028/). Shimizu et al. found that β-glucosylceramide activates microglia, leading to the phagocytosis of neurons in Gaucher disease, which highlights the detrimental effects of microglial activation in certain contexts (ref: Shimizu doi.org/10.1016/j.immuni.2023.01.008/). Chen et al. demonstrated that the neuronal NLRP3 inflammasome mediates neuroinflammatory responses, with microglial activation contributing to the overall inflammatory milieu (ref: Chen doi.org/10.1093/brain/). These studies underscore the dual role of microglia in both protective and harmful immune responses, suggesting that modulation of microglial activity could be a therapeutic strategy in neurodegenerative diseases.

Microglia are increasingly recognized for their role in CNS repair and regeneration following injury or disease. Parker et al. investigated the use of immunotoxin therapy combined with αCD40 costimulation to enhance immune responses against glioblastoma, demonstrating that microglial activation can be harnessed to improve therapeutic outcomes (ref: Parker doi.org/10.1126/scitranslmed.abn5649/). Zeng et al. introduced STARmap PLUS, which provides insights into the spatiotemporal dynamics of microglial responses in neurodegenerative conditions, potentially informing strategies for CNS repair (ref: Zeng doi.org/10.1038/s41593-022-01251-x/). Zheng et al. identified a lncRNA-encoded micropeptide that exacerbates microglia-mediated neuroinflammation in retinal ischemia/reperfusion injury, indicating that understanding microglial responses is crucial for developing effective regenerative therapies (ref: Zheng doi.org/10.1038/s41419-023-05617-2/). These findings highlight the potential for targeting microglial functions to enhance CNS repair mechanisms.

Microglia are implicated in various neurodevelopmental disorders, influencing both disease onset and progression. Shimizu et al. demonstrated that in Gaucher disease, the accumulation of β-glucosylceramide activates microglia, leading to neuronal phagocytosis and exacerbation of symptoms, highlighting the detrimental role of microglial activation in neurodevelopmental contexts (ref: Shimizu doi.org/10.1016/j.immuni.2023.01.008/). Hata et al. reported that early-life infections can reprogram retinal microglia, contributing to the development of age-related macular degeneration, suggesting that environmental factors can shape microglial functions and influence disease outcomes (ref: Hata doi.org/10.1172/JCI159757/). Additionally, Xie et al. explored the role of Helicobacter pylori-derived vesicles in AD pathogenesis, indicating that gut microbiota may interact with microglial functions in neurodevelopmental disorders (ref: Xie doi.org/10.1002/jev2.12306/). These studies underscore the complex interplay between microglia, environmental factors, and neurodevelopmental disorders.

The relationship between microglia and metabolic changes is gaining attention, particularly in the context of neurodegenerative diseases. Brioschi et al. developed a Cre-deleter line that allows for the specific targeting of microglia, providing insights into their metabolic profiles during development and disease (ref: Brioschi doi.org/10.1016/j.immuni.2023.01.028/). Shimizu et al. highlighted how the accumulation of β-glucosylceramide in Gaucher disease activates microglia, leading to metabolic alterations that exacerbate neuronal damage (ref: Shimizu doi.org/10.1016/j.immuni.2023.01.008/). Furthermore, Xie et al. discussed the role of gut microbiota in influencing microglial metabolism and its implications for neurodegenerative diseases, suggesting that metabolic changes in microglia can significantly impact disease progression (ref: Xie doi.org/10.1002/jev2.12306/). These findings emphasize the need to explore the metabolic aspects of microglial function in the context of neurodegenerative diseases.

Aging significantly impacts microglial function, contributing to neurodegenerative diseases. Zeng et al. introduced STARmap PLUS, a method that allows for the mapping of microglial transcriptional states in aging models, providing insights into the cellular changes that occur with age (ref: Zeng doi.org/10.1038/s41593-022-01251-x/). Qiao et al. found that the TREM2 H157Y mutation enhances soluble TREM2 production and reduces amyloid pathology, suggesting that genetic factors can influence microglial responses in aging (ref: Qiao doi.org/10.1186/s13024-023-00599-3/). Hata et al. reported that early-life infections can lead to long-term changes in microglial function, potentially predisposing individuals to age-related diseases such as macular degeneration (ref: Hata doi.org/10.1172/JCI159757/). These studies highlight the critical role of microglia in aging and their potential as therapeutic targets for age-related neurodegenerative diseases.