Microglia, the resident immune cells of the brain, play a pivotal role in neurodegenerative diseases, influencing both neuronal health and disease progression. Recent studies have highlighted the impact of type I interferon (IFN-I) signaling on microglial function, demonstrating that loss of the IFN-I receptor leads to phagolysosomal dysfunction and increased neuronal DNA damage (ref: Escoubas doi.org/10.1016/j.cell.2024.02.020/). In Alzheimer's disease (AD), xenografted human microglia exhibit diverse transcriptomic states in response to amyloid-beta pathology, revealing the complexity of microglial responses in human brains (ref: Mancuso doi.org/10.1038/s41593-024-01600-y/). Furthermore, a study on multiple sclerosis (MS) indicated that myeloid cell replacement can provide neuroprotection, suggesting that understanding the cellular mechanisms behind these therapies is crucial for developing effective treatments (ref: Mader doi.org/10.1038/s41593-024-01609-3/). The interplay between autoimmune conditions and neurodegenerative diseases is further emphasized by findings of lupus autoantibodies initiating neuroinflammation, which can lead to cognitive impairment (ref: Carroll doi.org/10.1038/s41590-024-01772-6/). Additionally, research into rejuvenating aged microglia has shown that enhancing their phagocytic ability could mitigate amyloid accumulation, highlighting potential therapeutic avenues (ref: Shin doi.org/10.1186/s13024-024-00715-x/). Lastly, an atlas of genetic overlaps between AD and immune-mediated diseases underscores the shared genetic architecture that may influence disease susceptibility (ref: Enduru doi.org/10.1038/s41380-024-02510-y/).

Microglial activation and inflammation are critical components in various neurological disorders, including ischemic stroke and major depressive disorder (MDD). Recent advancements in nanomedicine have introduced neutrophil membrane-camouflaged polyprodrug formulations that effectively suppress inflammation in ischemic stroke, demonstrating the potential for targeted delivery of anti-inflammatory agents (ref: Zhao doi.org/10.1002/adma.202311803/). In the context of Alzheimer's disease, hypothyroidism has been shown to impair microglial immune responses, exacerbating AD pathology through reduced activation of inflammatory pathways (ref: Kim doi.org/10.1126/sciadv.adi1863/). Interestingly, genetic studies in schizophrenia have revealed increased expression of inflammation-related genes in microglia, yet without clear signs of hyperactivation, suggesting a complex relationship between microglial state and disease phenotype (ref: Koskuvi doi.org/10.1038/s41380-024-02529-1/). Methodological advancements, such as a hierarchical Bayesian approach to Sholl analysis, have improved the quantification of microglial morphology, which is essential for understanding their functional roles in health and disease (ref: VonKaenel doi.org/10.1093/bioinformatics/). Furthermore, down-regulation of MKP-1 has been linked to protection against stress-induced neuroinflammation and depression-like behaviors, emphasizing the role of microglial signaling in mood disorders (ref: Geng doi.org/10.1038/s41398-024-02846-7/). Melatonin has also been identified as a protective agent against chronic stress-induced microglial pyroptosis, further supporting the therapeutic potential of modulating microglial activation (ref: Gao doi.org/10.1038/s41398-024-02887-y/).

Microglia are essential for synaptic pruning and plasticity, processes critical for brain development and function. Research has shown that microglial over-pruning of synapses is implicated in autism spectrum disorder (ASD), particularly in SCN2A-deficient mice, highlighting the neuro-immune interactions that may contribute to the disorder's pathophysiology (ref: Wu doi.org/10.1038/s41380-024-02518-4/). Additionally, an enriched early experience has been demonstrated to drive targeted microglial engulfment of miswired neural circuitry, suggesting that microglia can mediate experience-induced corrections in neural circuits (ref: Rogerson-Wood doi.org/10.1002/glia.24522/). The neurotoxic effects of environmental pollutants, such as polystyrene nanoplastics, have also been linked to microglial activation and memory impairment, indicating that microglial responses to external factors can significantly affect cognitive functions (ref: Paing doi.org/10.1016/j.scitotenv.2024.171681/). Furthermore, ALS-linked mutations in profilin-1 have been shown to impair vesicular degradation in iPSC-derived microglia, suggesting that genetic factors can influence microglial functionality and their role in neurodegenerative processes (ref: Funes doi.org/10.1038/s41467-024-46695-w/). Overall, these findings underscore the multifaceted roles of microglia in maintaining synaptic integrity and responding to both genetic and environmental challenges.

Therapeutic strategies targeting microglia are gaining traction in the treatment of neurodegenerative diseases. Recent studies utilizing single-nucleus RNA sequencing have elucidated the effects of genetic variation on gene expression across different brain cell types, revealing significant insights into the cellular mechanisms underlying Alzheimer's disease (ref: Fujita doi.org/10.1038/s41588-024-01685-y/). Additionally, the role of mesenchymal stromal cells (MSCs) in modulating microglial responses through secreted extracellular vesicles has been highlighted, showcasing their potential as a therapeutic avenue for neuroinflammation (ref: Larey doi.org/10.1016/j.bioactmat.2024.03.009/). The vascular endothelial growth factor-C (VEGF-C) has emerged as a promising candidate for enhancing lymphatic drainage and modulating neuroinflammation in stroke models, indicating its therapeutic potential in neurological disorders (ref: Boisserand doi.org/10.1084/jem.20221983/). Furthermore, the regulation of microglial activity through cholesterol metabolism has been explored, with findings suggesting that cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in tauopathy models (ref: Toral-Rios doi.org/10.1084/jem.20232000/). Lastly, the modulation of microRNA expression in microglia has been linked to the development of schizophrenia-like symptoms, emphasizing the need for further exploration of microRNA-targeted therapies (ref: Kaurani doi.org/10.1038/s44318-024-00067-8/). These studies collectively underscore the importance of targeting microglial function as a therapeutic strategy in various neurodegenerative conditions.

The genetic and molecular mechanisms governing microglial function are critical for understanding their roles in health and disease. Recent research has identified the NLRP3 inflammasome as a key player in microglial activation, with species-specific regulation impacting its physiological effects in CNS autoinflammatory diseases (ref: Koller doi.org/10.1016/j.celrep.2024.113852/). Additionally, the role of HDAC3 in regulating microglial proliferation and polarization after ischemic stroke has been elucidated, suggesting that targeting epigenetic regulators may offer therapeutic benefits (ref: Zhang doi.org/10.1126/sciadv.ade6900/). The structural connectome's genetic architecture has also been investigated, revealing significant genetic correlations with neuropsychiatric traits, which may influence microglial function and connectivity (ref: Wainberg doi.org/10.1038/s41467-024-46023-2/). Furthermore, innovative approaches such as optical control of actin dynamics in microglia have been developed, providing new tools to study microglial behavior and interactions (ref: Vepřek doi.org/10.1021/jacs.3c10776/). These findings highlight the intricate genetic and molecular landscape that shapes microglial responses and their implications for neurodegenerative diseases.

Microglial responses to neuroinflammation are critical in the context of ischemic stroke, where they can either exacerbate or mitigate damage. Recent studies have demonstrated that myricetin oligomers can enhance blood-brain barrier (BBB) restoration and promote autophagic processes, presenting a novel approach for treating ischemic stroke (ref: Liu doi.org/10.1021/acsnano.3c09532/). Additionally, VEGF-C has been shown to favor lymphatic drainage and modulate neuroinflammation, indicating its potential as a therapeutic target in stroke recovery (ref: Boisserand doi.org/10.1084/jem.20221983/). The role of neuroinflammation in exacerbating neurological dysfunction post-stroke has been underscored, with findings suggesting that the FDA-approved drug fingolimod may offer neuroprotective effects by targeting microglial activation (ref: Zhao doi.org/10.1002/adma.202311803/). Moreover, the interaction between tau proteins and the NLRP3 inflammasome has been linked to cognitive impairment and microglial activation, suggesting that targeting these pathways could alleviate neuroinflammation and improve outcomes (ref: Zhang doi.org/10.1002/ctm2.1623/). Collectively, these studies emphasize the dual role of microglia in stroke pathology and recovery, highlighting the need for targeted therapeutic strategies.

Microglial interactions with other cell types are crucial for maintaining brain homeostasis and responding to injury. Recent findings have shown that genetic variations can influence gene expression in different brain cell types, including microglia, which may have implications for Alzheimer's disease pathology (ref: Fujita doi.org/10.1038/s41588-024-01685-y/). The formation of cofilactin rods in response to inflammation has been linked to neurite degeneration, indicating that microglial interactions with neurons can lead to functional impairments in neurodegenerative conditions (ref: Uruk doi.org/10.1016/j.celrep.2024.113914/). Furthermore, mesenchymal stromal cells (MSCs) have been identified as potential modulators of microglial activity through their secreted extracellular vesicles, which may offer therapeutic benefits in neuroinflammation (ref: Larey doi.org/10.1016/j.bioactmat.2024.03.009/). Additionally, microglial over-pruning of synapses during development has been implicated in autism spectrum disorder, highlighting the importance of microglial-neuronal interactions in neurodevelopmental disorders (ref: Wu doi.org/10.1038/s41380-024-02518-4/). These studies underscore the significance of understanding microglial interactions with other cell types to develop targeted therapies for various neurological disorders.

Microglial responses to environmental factors play a significant role in the development of neurological disorders. Recent research has demonstrated that exposure to polystyrene microplastics can induce anxiety-like behaviors through the HRAS-derived PERK-NF-κB pathway, highlighting the impact of environmental pollutants on microglial function and mental health (ref: Li doi.org/10.1016/j.envint.2024.108543/). Additionally, studies on opioid use disorder have shown that long-access heroin self-administration leads to region-specific reductions in grey matter volume and increased microglial reactivity, suggesting that substance abuse can alter microglial dynamics and brain structure (ref: Cannella doi.org/10.1016/j.bbi.2024.03.003/). The interaction between tau proteins and the NLRP3 inflammasome has also been implicated in neuroinflammation, with findings indicating that tau-induced microglial activation can exacerbate cognitive decline (ref: Zhang doi.org/10.1002/ctm2.1623/). Furthermore, chronic stress has been linked to neuroinflammation and depression-like behaviors, with MKP-1 down-regulation in the hippocampus providing protective effects against these stress-induced changes (ref: Geng doi.org/10.1038/s41398-024-02846-7/). Lastly, vagus nerve stimulation has emerged as a promising neuroprotective strategy for ischemic stroke, demonstrating the potential for modulating microglial responses through environmental interventions (ref: Xia doi.org/10.1038/s41401-024-01245-4/). These findings underscore the importance of environmental factors in shaping microglial responses and their implications for neurological health.