Recent studies have elucidated the complex role of microglia in neuroinflammation and their activation in response to various stressors. Byun et al. demonstrated that stress hormones significantly increase the expression of the phagocytic receptor MERTK in astrocytes, promoting synapse phagocytosis, which could contribute to behavioral abnormalities associated with childhood neglect (ref: Byun doi.org/10.1016/j.immuni.2023.07.005/). Han et al. characterized the maturation of human microglia, revealing stage-specific transcriptomes and epigenetic landscapes that are crucial for understanding their functional roles in neuroinflammatory contexts (ref: Han doi.org/10.1016/j.immuni.2023.07.016/). Douglass et al. provided insights into the paradoxical effects of obesity-associated microglial activation, showing that while it exacerbates glucose intolerance, it also plays a role independent of body weight in glucose regulation (ref: Douglass doi.org/10.1016/j.cmet.2023.07.008/). Furthermore, Askin et al. and an additional review highlighted the detrimental interactions between microglia and T cells in tau-mediated neurodegeneration, suggesting that these interactions exacerbate neuroinflammatory responses in Alzheimer's disease (ref: Askin doi.org/10.1038/s41392-023-01563-9/; ref: Unknown doi.org/10.1038/s41593-023-01417-1/). Ralvenius et al. identified a novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs, which may reduce neuroinflammation, indicating potential therapeutic targets (ref: Ralvenius doi.org/10.1084/jem.20222105/). Dutta et al. further explored the inflammatory response induced by tau fibrils, linking TLR2 activation in microglia to neuroinflammation in Alzheimer's models (ref: Dutta doi.org/10.1172/JCI161987/). Rueda-Carrasco et al. demonstrated that microglia can ameliorate neuronal hyperactivity through synapse engulfment mechanisms, emphasizing their protective role in early Alzheimer's disease (ref: Rueda-Carrasco doi.org/10.15252/embj.2022113246/). Lastly, Zhou et al. highlighted the influence of dietary fiber and microbiota metabolite receptors on cognition and microglial morphology, suggesting a link between diet, gut microbiota, and neuroinflammation (ref: Zhou doi.org/10.1523/JNEUROSCI.0724-23.2023/).

Microglia play a pivotal role in the pathophysiology of neurodegenerative diseases, particularly Alzheimer's disease (AD). Jorfi et al. developed a three-dimensional human neuroimmune axis model that revealed increased infiltration of T cells into AD cultures, highlighting the interaction between peripheral immune cells and brain-resident microglia (ref: Jorfi doi.org/10.1038/s41593-023-01415-3/). Askin et al. further emphasized the neurotoxic interplay between infiltrated T cells and microglia in tau-mediated neurodegeneration, suggesting that this interaction exacerbates neuroinflammatory responses (ref: Askin doi.org/10.1038/s41392-023-01563-9/). Comerota et al. explored the therapeutic potential of oleoylethanolamide in AD models, demonstrating its ability to facilitate PPARα and TFEB signaling, which attenuates Aβ pathology (ref: Comerota doi.org/10.1186/s13024-023-00648-x/). Rueda-Carrasco et al. also contributed to the understanding of microglial roles in AD by showing that synapse engulfment via PtdSer-TREM2 can ameliorate neuronal hyperactivity, a hallmark of early AD (ref: Rueda-Carrasco doi.org/10.15252/embj.2022113246/). Fan et al. utilized single-cell transcriptomics to investigate cellular responses in spinal cord injury, providing insights into the heterogeneity of microglial responses in neurodegenerative contexts (ref: Fan doi.org/10.1038/s41467-023-40513-5/). Haukedal et al. examined the neurotoxic effects of microglial metabolism alterations in frontotemporal dementia, revealing how specific genetic backgrounds can influence microglial behavior and neurotoxicity (ref: Haukedal doi.org/10.1016/j.bbi.2023.07.024/).

The interactions between microglia and other immune cells are critical in shaping neuroinflammatory responses in the brain. Askin et al. highlighted the neurotoxic interplay between activated microglia and infiltrated T cells in tau-mediated neurodegeneration, suggesting that this interaction is a key driver of neuroinflammation in Alzheimer's disease (ref: Askin doi.org/10.1038/s41392-023-01563-9/). In a review, the complexities of immune signaling pathways in Alzheimer's disease were discussed, emphasizing the roles of both innate and adaptive immune cells, including T cells, in influencing AD neuropathogenesis (ref: Unknown doi.org/10.1038/s41593-023-01417-1/). Han et al. characterized the maturation of human microglia and their regulatory networks, which are influenced by the brain environment, thereby providing insights into how microglial phenotypes can interact with other immune cells (ref: Han doi.org/10.1016/j.immuni.2023.07.016/). Douglass et al. examined the role of microglia in glucose regulation, revealing that microglial inflammatory activation can paradoxically improve glucose tolerance, indicating a complex relationship between metabolic processes and immune responses (ref: Douglass doi.org/10.1016/j.cmet.2023.07.008/). Additionally, Fan et al. utilized single-cell transcriptomics to explore cellular responses in spinal cord injury, shedding light on the heterogeneous responses of microglia and their interactions with other immune cells in the context of injury (ref: Fan doi.org/10.1038/s41467-023-40513-5/).

Understanding the molecular mechanisms underlying microglial function is crucial for elucidating their roles in health and disease. Fan et al. employed single-cell transcriptomics to reveal region-heterogeneous responses in the spinal cord following injury, highlighting the dynamic nature of microglial responses (ref: Fan doi.org/10.1038/s41467-023-40513-5/). Rueda-Carrasco et al. investigated the molecular determinants of microglial synapse engulfment, demonstrating that neuronal hyperactivity in Alzheimer's disease models is associated with the externalization of phosphatidylserine, a signal recognized by microglia (ref: Rueda-Carrasco doi.org/10.15252/embj.2022113246/). Haukedal et al. explored the alterations in microglial metabolism and inflammatory profiles in a model of frontotemporal dementia, revealing how these changes contribute to neurotoxicity (ref: Haukedal doi.org/10.1016/j.bbi.2023.07.024/). Additionally, Rao et al. discussed the role of astrocytic fragmented mitochondria in regulating neuroinflammation and addiction behaviors, emphasizing the crosstalk between neurons, astrocytes, and microglia (ref: Rao doi.org/10.1016/j.bbi.2023.07.030/). These studies collectively enhance our understanding of the intricate molecular networks that govern microglial functions and their implications in neurodegenerative diseases.

Therapeutic strategies targeting microglia are emerging as promising avenues for treating neurodegenerative diseases. Fruhwürth et al. reported that herpes simplex virus type 1 (HSV1) infection down-regulates TREM2 expression in microglia, implicating this pathway in antiviral defense and suggesting potential therapeutic targets for enhancing microglial function in viral infections (ref: Fruhwürth doi.org/10.1126/sciadv.adf5808/). Haukedal et al. investigated the neurotoxic effects of microglial metabolism alterations in frontotemporal dementia, revealing that conditioned media from specific microglial genotypes can influence neural outgrowth and suggesting that modulating microglial function could have therapeutic benefits (ref: Haukedal doi.org/10.1016/j.bbi.2023.07.024/). Additionally, Rao et al. highlighted the role of astrocytes in morphine addiction through neuroinflammation, indicating that targeting the interactions between astrocytes and microglia may provide new therapeutic strategies for addiction-related disorders (ref: Rao doi.org/10.1016/j.bbi.2023.07.030/). These findings underscore the potential of developing therapies that modulate microglial activity to ameliorate neurodegenerative conditions and enhance brain health.

Microglia are increasingly recognized for their role in synaptic function and plasticity, particularly in the context of neurodegenerative diseases. Rueda-Carrasco et al. demonstrated that microglia can ameliorate neuronal hyperactivity in Alzheimer's disease models through synapse engulfment mechanisms, specifically via the recognition of phosphatidylserine, which serves as an 'eat-me' signal (ref: Rueda-Carrasco doi.org/10.15252/embj.2022113246/). This study highlights the protective role of microglia in maintaining synaptic integrity during early stages of Alzheimer's disease. Additionally, Haukedal et al. explored how alterations in microglial metabolism and inflammatory profiles contribute to neurotoxicity in frontotemporal dementia, suggesting that dysfunctional microglial activity can adversely affect synaptic health (ref: Haukedal doi.org/10.1016/j.bbi.2023.07.024/). Furthermore, Rao et al. discussed the crosstalk between neurons, astrocytes, and microglia in the context of morphine addiction, indicating that synaptic alterations may also be influenced by neuroinflammatory processes involving microglia (ref: Rao doi.org/10.1016/j.bbi.2023.07.030/). Collectively, these studies underscore the critical role of microglia in regulating synaptic function and their potential as therapeutic targets for neurodegenerative diseases.

Microglia are essential players in the brain's response to injury and repair processes. Haukedal et al. investigated the role of microglial metabolism and inflammatory profiles in frontotemporal dementia, revealing that specific microglial genotypes can influence neurotoxic effects and neural outgrowth, which are critical for recovery following brain injury (ref: Haukedal doi.org/10.1016/j.bbi.2023.07.024/). Additionally, Rao et al. highlighted the crosstalk among neurons, astrocytes, and microglia in morphine addiction, suggesting that neuroinflammation can impact recovery and repair mechanisms in the central nervous system (ref: Rao doi.org/10.1016/j.bbi.2023.07.030/). These findings emphasize the importance of microglial function in mediating the brain's response to injury and their potential as therapeutic targets for enhancing recovery processes. Furthermore, the studies collectively suggest that understanding the molecular mechanisms governing microglial responses to injury could lead to novel interventions aimed at promoting brain repair and mitigating neurodegenerative processes.

The metabolic state of microglia is crucial for their functional roles in the brain, particularly in the context of neuroinflammation and neurodegeneration. Haukedal et al. examined how alterations in microglial metabolism and inflammatory profiles contribute to neurotoxicity in a model of frontotemporal dementia, indicating that metabolic dysfunction can exacerbate neurodegenerative processes (ref: Haukedal doi.org/10.1016/j.bbi.2023.07.024/). Additionally, Rao et al. discussed the role of astrocytic fragmented mitochondria in regulating neuroinflammation and addiction behaviors, emphasizing the interplay between microglial and astrocytic metabolism in the central nervous system (ref: Rao doi.org/10.1016/j.bbi.2023.07.030/). These studies highlight the importance of understanding microglial metabolism as a potential therapeutic target for modulating their function in neurodegenerative diseases and enhancing brain health.