Microglial activation plays a crucial role in neuroinflammation, particularly in the context of neurodegenerative diseases such as Alzheimer's disease (AD). Recent studies have highlighted the significance of the cGAS-IFN pathway in modulating microglial responses. For instance, Udeochu et al. demonstrated that tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience, suggesting that targeting this pathway could enhance neuronal resilience against AD-related insults (ref: Udeochu doi.org/10.1038/s41593-023-01315-6/). In another study, Festa et al. revealed that activated microglia inhibit neuronal autophagy through CCR5 signaling, which is critical for clearing toxic proteins in neurodegeneration (ref: Festa doi.org/10.1016/j.neuron.2023.04.006/). Furthermore, the aging process has been shown to perturb microglial functions, as Dong et al. identified aging-associated transcripts that correlate with neurodegeneration, emphasizing the need to understand microglial behavior in aging (ref: Dong doi.org/10.1038/s43587-022-00205-z/). These findings collectively underscore the complex interplay between microglial activation, neuroinflammation, and neurodegenerative processes, highlighting potential therapeutic targets for intervention. Moreover, the impact of external factors such as sleep deprivation on microglial reactivity has been explored. Parhizkar et al. found that chronic sleep deprivation exacerbates microglial reactivity and amyloid-beta deposition in mouse models of AD, indicating that lifestyle factors can significantly influence neuroinflammatory responses (ref: Parhizkar doi.org/10.1126/scitranslmed.ade6285/). Additionally, the role of microglia in response to viral infections has been investigated, with Zheng et al. demonstrating that the autophagy receptor SHISA9 modulates virus-induced neuroinflammation, further illustrating the diverse functions of microglia in maintaining CNS homeostasis (ref: Zheng doi.org/10.1038/s41564-023-01357-3/). These studies collectively highlight the multifaceted roles of microglia in neuroinflammation and their potential as therapeutic targets in neurodegenerative diseases.

Microglia are increasingly recognized for their pivotal role in neurodegenerative diseases, particularly in Alzheimer's disease (AD) and related pathologies. Koutsodendris et al. provided compelling evidence that the genetic removal of neuronal APOE4, a major risk factor for late-onset AD, significantly reduces tau pathology, gliosis, and neurodegeneration, underscoring the importance of microglial interactions in these processes (ref: Koutsodendris doi.org/10.1038/s43587-023-00368-3/). This study aligns with findings from Festa et al., who demonstrated that activated microglia inhibit neuronal autophagy, a critical pathway for clearing toxic aggregates in neurodegenerative conditions (ref: Festa doi.org/10.1016/j.neuron.2023.04.006/). Furthermore, the activation of hypothalamic-enhanced adult-born neurons has been shown to restore cognitive and affective functions in AD models, indicating that modulating neurogenesis may offer therapeutic avenues for mitigating neurodegenerative deficits (ref: Li doi.org/10.1016/j.stem.2023.02.006/). The interplay between microglial function and neurodegeneration is further complicated by factors such as aging and sex differences. Zhang et al. reported that progranulin deficiency leads to sex-dependent alterations in microglial responses to demyelination, highlighting the need to consider biological sex in neurodegenerative research (ref: Zhang doi.org/10.1007/s00401-023-02578-w/). Additionally, the study by Dong et al. on aging-associated microglial transcripts revealed that changes in microglial function with age contribute to neurodegenerative processes, emphasizing the importance of understanding microglial dynamics across the lifespan (ref: Dong doi.org/10.1038/s43587-022-00205-z/). Collectively, these studies illustrate the critical role of microglia in neurodegenerative diseases and the potential for therapeutic strategies targeting microglial activation and function.

Microglia are integral to synaptic plasticity, influencing both the formation and elimination of synapses. Hashimoto et al. demonstrated that microglia enable cross-modal plasticity by removing inhibitory synapses, a process crucial for the brain's adaptation to sensory deprivation (ref: Hashimoto doi.org/10.1016/j.celrep.2023.112383/). This finding highlights the role of microglia in reshaping neural circuits and suggests that their activity is essential for recovery from sensory loss. Similarly, Wen et al. reported that the complement inhibitor CD59 is necessary for GABAergic synaptic transmission in the dentate gyrus, indicating that microglial pruning of excitatory synapses can also affect inhibitory signaling (ref: Wen doi.org/10.1016/j.celrep.2023.112349/). Moreover, the impact of external factors on microglial function and synaptic integrity has been explored. Parhizkar et al. found that sleep deprivation exacerbates microglial reactivity and amyloid-beta deposition, suggesting that lifestyle factors can significantly influence synaptic health and plasticity in the context of neurodegenerative diseases (ref: Parhizkar doi.org/10.1126/scitranslmed.ade6285/). Additionally, Kannan et al. investigated the role of HIV-1 Tat in mediating microglial ferroptosis, revealing that microglial activation can lead to detrimental outcomes in neuronal health (ref: Kannan doi.org/10.1016/j.redox.2023.102689/). These findings collectively underscore the complex interplay between microglial function, synaptic plasticity, and external influences, highlighting the potential for targeting microglial activity to enhance synaptic health and cognitive function.

Microglia play a critical role in the immune response within the central nervous system (CNS), influencing both neuroinflammation and neuroprotection. Thiesler et al. highlighted the significance of the polysialic acid-Siglec-16 axis in proinflammatory macrophage activation, linking this pathway to glioblastoma progression and patient survival (ref: Thiesler doi.org/10.1158/1078-0432.CCR-22-1488/). This study emphasizes the importance of understanding microglial interactions with tumor-associated macrophages in the context of brain tumors. Additionally, Chen et al. demonstrated that M1 microglia-derived exosomes promote the activation of resting microglia, amplifying proangiogenic effects in retinal diseases, indicating that microglial communication can significantly impact disease progression (ref: Chen doi.org/10.7150/ijbs.79784/). Furthermore, Kuo et al. explored the modulation of microglial polarization by interferon-beta, showing that this cytokine can ameliorate delayed tPA-exacerbated brain injury in ischemic stroke models (ref: Kuo doi.org/10.3389/fimmu.2023.1148069/). This highlights the potential for therapeutic strategies targeting microglial polarization to enhance recovery from CNS injuries. Zeng et al. utilized single-cell analyses to reveal dynamic transcriptional changes in microglia following ischemic stroke, providing insights into the temporal aspects of microglial activation and their role in the immune response (ref: Zeng doi.org/10.3389/fimmu.2023.1114663/). Collectively, these studies underscore the multifaceted roles of microglia in immune responses within the CNS and their potential as therapeutic targets in various neurological conditions.

The regulation of microglial gene expression and epigenetic modifications is crucial for understanding their role in neuroinflammation and neurodegeneration. Snellman et al. investigated the APOE ε4 gene dose effect on neuroinflammation and beta-amyloid biomarkers in cognitively unimpaired elderly individuals, revealing that neuroinflammation is present even in early stages of Alzheimer's disease (ref: Snellman doi.org/10.1186/s13195-023-01209-6/). This study highlights the importance of genetic factors in modulating microglial responses and their implications for disease risk. Huang et al. further explored epigenetic reprogramming in microglia, demonstrating that histone H3K27 acetylation can enhance immune regulation and memory formation in response to environmental stimuli (ref: Huang doi.org/10.3389/fimmu.2023.1052925/). Additionally, Filipello et al. examined the functional defects in lysosomal function and lipid metabolism in human microglia harboring TREM2 mutations, linking these genetic variations to increased risk for Alzheimer's disease and frontotemporal dementia (ref: Filipello doi.org/10.1007/s00401-023-02568-y/). This underscores the critical role of microglial gene expression in maintaining CNS homeostasis and responding to pathological challenges. Duwat et al. developed an AAV-based model of tauopathy to study microglial involvement in tau pathology, providing a platform for investigating the molecular mechanisms underlying neurodegeneration (ref: Duwat doi.org/10.1016/j.nbd.2023.106116/). Collectively, these studies emphasize the importance of gene expression and epigenetic regulation in microglial function and their implications for neurodegenerative diseases.

Microglia are essential for brain development and aging, influencing neuroinflammatory processes and neuronal health. Swanson et al. examined the relationship between microglial activation and TDP-43 pathology in amyotrophic lateral sclerosis (ALS), finding significant upregulation of microglial markers in regions with high TDP-43 burden (ref: Swanson doi.org/10.1186/s40478-023-01561-6/). This study highlights the role of microglia in responding to neurodegenerative pathology and their potential as therapeutic targets. Liu et al. investigated the NOD-like receptor NLRC5 in Parkinson's disease models, demonstrating that its expression correlates with neuroinflammation and neuronal survival, suggesting that microglial responses can significantly impact disease outcomes (ref: Liu doi.org/10.1186/s12974-023-02755-4/). Moreover, Orso et al. conducted a systematic review and meta-analysis on the effects of prenatal and early life stress on microglial density and morphology, revealing conflicting results that underscore the complexity of microglial responses to environmental stressors during development (ref: Orso doi.org/10.1016/j.neubiorev.2023.105202/). Spiteri et al. tracked microglial and monocyte transcriptomics during flavivirus infection, highlighting the dynamic changes in microglial function in response to viral challenges (ref: Spiteri doi.org/10.1186/s40478-023-01547-4/). Collectively, these studies emphasize the critical role of microglia in development and aging, as well as their potential implications for neurodevelopmental and neurodegenerative disorders.

Emerging therapeutic strategies targeting microglia hold promise for treating neurodegenerative diseases. Su et al. developed an erythrocyte membrane-coated nanotheranostic system designed to regulate the immune environment in Alzheimer's disease, demonstrating the potential for targeted drug delivery across the blood-brain barrier (ref: Su doi.org/10.1002/advs.202301361/). This innovative approach highlights the importance of microglial modulation in therapeutic interventions. Kumar et al. identified microRNA expression in extracellular vesicles as a novel blood-based biomarker for Alzheimer's disease, providing insights into the role of microglia in disease progression and potential diagnostic applications (ref: Kumar doi.org/10.1002/alz.13055/). Additionally, Zhang et al. explored dendrimer-enabled targeted delivery to mitigate glutamate excitotoxicity in a rabbit model of cerebral palsy, emphasizing the importance of targeting activated microglia and astrocytes to improve therapeutic efficacy (ref: Zhang doi.org/10.1016/j.jconrel.2023.04.017/). Furthermore, Lin et al. demonstrated that rapamycin alleviates protein aggregates and reduces neuroinflammation in a model of globoid cell leukodystrophy, highlighting the potential of mTOR inhibitors in modulating microglial activity and improving outcomes in neurodegenerative diseases (ref: Lin doi.org/10.3390/cells12070993/). Collectively, these studies underscore the potential of targeting microglia in developing effective therapeutic strategies for neurodegenerative conditions.