Microglial cells play a crucial role in the central nervous system's immune response, particularly in neuroinflammatory conditions. Recent studies have highlighted the negative impact of the APOE4 allele on microglial function in Alzheimer's disease (AD). Specifically, Yin et al. demonstrated that microglial APOE4 impairs the MGnD response to neurodegeneration, with deletion of this allele restoring neuroprotective phenotypes in tau transgenic mice and reducing pathology in APP/PS1 models (ref: Yin doi.org/10.1038/s41590-023-01627-6/). In glioblastoma, Pang et al. identified the Kunitz-type protease inhibitor TFPI2 as a key factor linking glioblastoma stem cells and immunosuppressive microglia, promoting tumor growth through the activation of the STAT3 pathway (ref: Pang doi.org/10.1038/s41590-023-01605-y/). Additionally, Zhang et al. explored the therapeutic potential of TMEM164, showing that its overexpression in astrocytes can inhibit neurotoxic reactive astrocyte induction and prevent neuronal loss in models of Parkinson's and Alzheimer's diseases (ref: Zhang doi.org/10.1038/s42255-023-00887-8/). These findings underscore the complex interplay between microglial function and neuroinflammation, revealing potential therapeutic targets for neurodegenerative disorders. The aging of microglia is another critical area of research, as it influences their response to neuroinflammation. Li et al. mapped transcriptional and epigenetic changes in microglia from young to aged mice, revealing alterations that increase susceptibility to brain dysfunction (ref: Li doi.org/10.1038/s43587-023-00479-x/). Furthermore, the study by Monsorno et al. on the loss of the MCT4 transporter in microglia highlighted its role in synaptic pruning and behavioral outcomes, indicating that microglial aging can lead to significant developmental and functional deficits (ref: Monsorno doi.org/10.1038/s41467-023-41502-4/). Collectively, these studies illustrate the multifaceted roles of microglia in neuroinflammation and neurodegeneration, emphasizing the need for targeted interventions to modulate their activity.

Microglia are increasingly recognized for their role in neurodegenerative diseases, particularly Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Gazestani et al. provided insights into early AD pathology by generating a single-nucleus atlas from cortical biopsies, identifying transient cell states that may contribute to disease progression (ref: Gazestani doi.org/10.1016/j.cell.2023.08.005/). This study complements Yang et al.'s work, which characterized genetic variants associated with AD in microglia, revealing that candidate cis-regulatory elements are enriched for AD heritability (ref: Yang doi.org/10.1038/s41588-023-01506-8/). Both studies highlight the importance of understanding microglial genetics and cellular states in the context of AD pathology. In ALS, Vahsen et al. explored the effects of the C9orf72 mutation on microglial function, demonstrating that iPSC-derived microglia from ALS patients exhibit pro-inflammatory characteristics that are toxic to motor neurons (ref: Vahsen doi.org/10.1038/s41467-023-41603-0/). This finding aligns with the broader theme of microglial activation contributing to neurodegeneration across various diseases. Additionally, the study by Zhuang et al. on noise-induced hearing loss revealed that microglial abnormalities precede cognitive decline, suggesting that microglial dysfunction may serve as an early indicator of neurodegenerative processes (ref: Zhuang doi.org/10.1016/j.bbi.2023.09.002/). Together, these studies underscore the critical role of microglia in neurodegenerative diseases and the potential for targeting microglial pathways in therapeutic strategies.

The aging of microglia is a significant factor influencing their function and response to neurodegenerative processes. Recent research by Li et al. has mapped the transcriptional and epigenetic changes in microglia from 3 to 24 months of age, revealing that aging alters their reactivity and increases susceptibility to brain dysfunction (ref: Li doi.org/10.1038/s43587-023-00479-x/). This study highlights the importance of understanding microglial aging at a single-cell resolution, which can provide insights into their role in neurodegenerative diseases. Furthermore, the work by Monsorno et al. demonstrated that the loss of the MCT4 transporter in microglia leads to defective synaptic pruning and anxiety-like behavior in mice, indicating that microglial dysfunction can have profound effects on brain development and behavior (ref: Monsorno doi.org/10.1038/s41467-023-41502-4/). Additionally, the study by Sun et al. revealed that maternal diet during early gestation influences postnatal microglial activity, specifically in the context of taste activity-dependent pruning (ref: Sun doi.org/10.1084/jem.20212476/). This finding suggests that environmental factors can modulate microglial function and potentially impact neurodevelopment. The research on microglial aging and cellular dynamics emphasizes the need for further investigation into how these cells adapt over time and how their dysfunction may contribute to neurodegenerative diseases.

Microglial response to injury is critical for brain repair mechanisms, and recent studies have explored various strategies to modulate this response. Zhang et al. developed self-assembling peptide nanofibers that protect against retinal ischemia-reperfusion injury by regulating microglial polarization and inhibiting oxidative stress (ref: Zhang doi.org/10.1002/advs.202302909/). This innovative approach highlights the potential for using biomaterials to influence microglial behavior and promote recovery after injury. In a different context, Yin et al. investigated the delivery of neural precursor cells in hyperlipidemic mice, finding that while acute cerebroprotection was achieved, long-term recovery was hindered by pro-inflammatory responses (ref: Yin doi.org/10.1186/s12974-023-02894-8/). This underscores the complexity of microglial interactions in the context of injury and repair. Moreover, Wang et al. introduced a novel approach using nanobubbles to modulate microglia-neuron interactions in epilepsy, suggesting that targeting microglial activation could provide therapeutic benefits for controlling seizures (ref: Wang doi.org/10.1016/j.biomaterials.2023.122302/). The differential effects of regulatory T cells on microglial and astrocyte reactivity in neuropathic pain models, as shown by Fiore et al., further illustrate the intricate interplay between immune cells and microglia in the context of injury and pain management (ref: Fiore doi.org/10.3390/cells12182317/). Collectively, these studies emphasize the importance of understanding microglial responses to injury and the potential for therapeutic interventions to enhance repair mechanisms.

Genetic and epigenetic factors play a crucial role in shaping microglial function and their involvement in neurodegenerative diseases. Yang et al. focused on the functional characterization of Alzheimer's disease genetic variants in microglia, identifying candidate cis-regulatory elements that are significantly enriched for AD heritability (ref: Yang doi.org/10.1038/s41588-023-01506-8/). This study highlights the importance of integrating genetic information with microglial-specific epigenomic data to understand the mechanisms underlying AD pathology. Similarly, Gazestani et al. provided insights into early AD pathology by generating a single-nucleus atlas from cortical biopsies, revealing transient cell states that may contribute to disease progression (ref: Gazestani doi.org/10.1016/j.cell.2023.08.005/). The aging process also affects microglial epigenetics, as demonstrated by Li et al., who mapped transcriptional and epigenetic changes in microglia across different ages (ref: Li doi.org/10.1038/s43587-023-00479-x/). This research underscores the need to explore how aging-related epigenetic modifications can influence microglial reactivity and their role in neurodegenerative diseases. Furthermore, the study by Sun et al. on maternal diet during early gestation suggests that environmental factors can also impact microglial function through epigenetic mechanisms (ref: Sun doi.org/10.1084/jem.20212476/). Together, these studies emphasize the intricate relationship between genetic, epigenetic, and environmental influences on microglial biology.

The gut-brain axis is increasingly recognized for its role in modulating neuroinflammation and microglial function. Xia et al. demonstrated that Bacteroides fragilis, a gut microbiota component, activates microglia and triggers pathogenesis in Alzheimer's disease models, suggesting a direct link between gut dysbiosis and neuroinflammation (ref: Xia doi.org/10.1038/s41467-023-41283-w/). This finding highlights the potential for targeting gut microbiota as a therapeutic strategy for neurodegenerative diseases. Additionally, the study by Monsorno et al. on the loss of the MCT4 transporter in microglia revealed that metabolic dysfunction can impact synaptic pruning and behavior, further emphasizing the importance of metabolic interactions between gut microbiota and microglial function (ref: Monsorno doi.org/10.1038/s41467-023-41502-4/). Moreover, the research by Sun et al. on maternal diet during early gestation indicated that dietary factors can influence microglial activity and development, potentially affecting the gut-brain axis (ref: Sun doi.org/10.1084/jem.20212476/). This interplay between diet, gut microbiota, and microglial function underscores the complexity of the gut-brain axis and its implications for neurodevelopment and neurodegenerative diseases. Collectively, these studies suggest that modulating gut microbiota and dietary factors may offer novel therapeutic avenues for addressing microglial dysfunction in neurodegenerative disorders.

Identifying therapeutic targets involving microglia is a critical area of research in neurodegenerative diseases. Zhang et al. explored the potential of TMEM164 as a therapeutic target, demonstrating that its overexpression in astrocytes can inhibit neurotoxic reactive astrocyte induction and prevent neuronal loss in models of Parkinson's and Alzheimer's diseases (ref: Zhang doi.org/10.1038/s42255-023-00887-8/). This study highlights the importance of astrocyte-microglia interactions in neuroprotection and suggests that targeting astrocytic pathways may offer therapeutic benefits. Similarly, Yin et al. identified the microglial APOE4-ITGB8-TGFβ pathway as a negative regulator of the microglial response in Alzheimer's disease, proposing that blocking this signaling could restore neuroprotective microglial phenotypes (ref: Yin doi.org/10.1038/s41590-023-01627-6/). In glioblastoma, Pang et al. revealed that the Kunitz-type protease inhibitor TFPI2 connects glioblastoma stem cells and immunosuppressive microglia, promoting tumor growth via the STAT3 pathway (ref: Pang doi.org/10.1038/s41590-023-01605-y/). This finding suggests that targeting TFPI2 could disrupt the tumor microenvironment and enhance therapeutic efficacy. Furthermore, the aging of microglia, as explored by Li et al., indicates that age-related changes in microglial function could also serve as potential therapeutic targets for mitigating neurodegenerative processes (ref: Li doi.org/10.1038/s43587-023-00479-x/). Together, these studies underscore the importance of targeting microglial pathways and their interactions with other cell types in developing effective therapies for neurodegenerative diseases.

Microglial interactions with other cell types are crucial for maintaining brain homeostasis and responding to injury. Recent studies have highlighted the complex relationships between microglia, neurons, and other immune cells. For instance, Zhang et al. developed self-assembling peptide nanofibers that modulate microglial polarization and inhibit oxidative stress in retinal ischemia-reperfusion injury, showcasing the potential for biomaterials to influence microglial behavior (ref: Zhang doi.org/10.1002/advs.202302909/). This research emphasizes the importance of microglial-neuron interactions in the context of injury and repair. Additionally, Fiore et al. investigated the effects of regulatory T cells on microglial and astrocyte reactivity in neuropathic pain models, revealing that Treg treatment can suppress pain hypersensitivity and improve exploratory behaviors in mice (ref: Fiore doi.org/10.3390/cells12182317/). This study highlights the role of immune cell interactions in modulating microglial activity and pain responses. Furthermore, Wang et al. explored the use of nanobubbles to modulate microglia-neuron interactions in epilepsy, suggesting that targeting microglial activation could provide therapeutic benefits for controlling seizures (ref: Wang doi.org/10.1016/j.biomaterials.2023.122302/). Together, these studies underscore the significance of microglial interactions with other cell types in both health and disease, pointing to potential therapeutic strategies that leverage these relationships.