Microglial cells play a crucial role in maintaining brain homeostasis and responding to neuroinflammation. Recent studies have highlighted the impact of meningeal lymphatics on microglial function, demonstrating that their dysfunction can lead to altered synaptic physiology and memory deficits (ref: Kim doi.org/10.1016/j.cell.2025.02.022/). In the context of COVID-19, research indicates that microglia are significantly involved in the neuroinflammatory response associated with systemic inflammation, linking microglial dysfunction to neurological abnormalities observed in patients (ref: Fekete doi.org/10.1038/s41593-025-01871-z/). Furthermore, single-cell transcriptomic analyses in amyotrophic lateral sclerosis (ALS) have revealed changes in glial states and inflammatory signaling pathways, underscoring the importance of microglial activation in neurodegenerative diseases (ref: Zelic doi.org/10.1016/j.immuni.2025.02.024/). The identification of disease-associated endothelial cell subsets in neurodegeneration further emphasizes the interconnectedness of microglial and vascular responses in maintaining blood-brain barrier integrity (ref: Omar doi.org/10.1038/s41593-025-01914-5/). Additionally, novel mRNA isoforms in human microglia have refined our understanding of genetic associations with neurodegeneration, revealing potential causal genes linked to various diseases (ref: Unknown doi.org/10.1038/s41588-025-02112-6/).

The mechanisms underlying neurodegenerative diseases are complex and multifaceted, with microglial involvement being a significant factor. Long-read RNA sequencing has provided insights into the genetic regulation of splicing in microglia, which is crucial for understanding their role in neurodegenerative conditions (ref: Humphrey doi.org/10.1038/s41588-025-02099-0/). The advent of spatial transcriptomics has further advanced our understanding of tissue regionalization and gene expression dynamics, allowing for a more nuanced view of cellular interactions in neurodegeneration (ref: Yang doi.org/10.1038/s41592-025-02622-5/). Multi-cohort cerebrospinal fluid proteomics has identified robust molecular signatures across the Alzheimer's disease continuum, revealing dysregulation of numerous proteins that could serve as biomarkers for early diagnosis (ref: Ali doi.org/10.1016/j.neuron.2025.02.014/). Additionally, the role of the APOE genotype in determining the pathological landscape of Alzheimer's disease has been elucidated, with findings indicating that APOE4 carriers exhibit distinct inflammatory signatures and altered synaptic pathways (ref: Li doi.org/10.1016/j.neuron.2025.02.017/). The interplay between immune responses and neurodegeneration is further highlighted by studies examining the effects of gut microbiome dysbiosis on immune cell dynamics in brain metastasis (ref: Golomb doi.org/10.1016/j.celrep.2025.115356/).

Recent advancements in genetic and molecular research have significantly enhanced our understanding of microglial biology and their role in neurodegeneration. The Microglia Genomic Atlas (MiGA) has emerged as a comprehensive resource, detailing genetic and transcriptomic variations in human microglia across various disease states, thereby identifying potential causal genes linked to neurodegenerative and psychiatric disorders (ref: Unknown doi.org/10.1038/s41588-025-02112-6/). Additionally, therapeutic strategies utilizing RNA delivery systems have shown promise in alleviating neuroinflammatory conditions, highlighting the potential of RNA therapeutics in modulating microglial responses (ref: Gao doi.org/10.1002/advs.202414559/). These findings underscore the importance of understanding the genetic underpinnings of microglial function, as they may offer novel targets for therapeutic intervention in neurodegenerative diseases.

Microglial responses to injury are critical for brain repair and recovery, with recent studies elucidating the mechanisms involved. Research has shown that CKLF1 disrupts microglial efferocytosis following acute ischemic stroke, impairing the clearance of apoptotic cells and exacerbating inflammation (ref: Fan doi.org/10.1038/s41418-025-01475-x/). Furthermore, itaconate has been identified as a metabolite that restrains proinflammatory activation of microglia after traumatic brain injury, suggesting a potential therapeutic avenue for mitigating secondary brain damage (ref: Liu doi.org/10.1126/scitranslmed.adn2635/). The heterogeneity of ALS has been characterized through deep multiomics classifiers, revealing distinct molecular subtypes associated with microglial activation and neuroinflammation (ref: O'Neill doi.org/10.1016/j.celrep.2025.115402/). Additionally, studies on cGAMP-mediated mechanisms have highlighted the role of microglia in blood-retinal barrier breakdown, indicating their involvement in neuroinflammatory processes across different contexts (ref: Ge doi.org/10.1186/s12974-025-03391-w/).

The role of microglia in cognitive and behavioral outcomes has garnered increasing attention, with studies demonstrating their influence on neurodevelopment and cognitive function. Voluntary wheel exercise has been shown to improve learning and memory impairments associated with hippocampal Hb-α deficiency by reducing microglial activation and reversing synaptic damage (ref: Wang doi.org/10.1016/j.bbi.2025.03.010/). Additionally, transforming growth factor β1 (TGF-β1) has been identified as a neuroprotective agent that alleviates ischemic demyelination by regulating microglial lipid metabolism, thereby mitigating cognitive deficits (ref: Xie doi.org/10.1161/STROKEAHA.124.048206/). The activation of the aryl hydrocarbon receptor (AhR) has also been linked to reduced microglial inflammation in graft-versus-host disease, further emphasizing the importance of microglial modulation in behavioral outcomes (ref: Zähringer doi.org/10.1182/bloodadvances.2024015000/). These findings highlight the intricate relationship between microglial activity and cognitive processes, suggesting potential therapeutic strategies targeting microglial function to improve cognitive health.

Therapeutic strategies targeting microglia have emerged as a promising avenue for addressing neurodegenerative diseases and related conditions. Research has demonstrated that activated microglia mediate significant changes in motor neuron health and muscle wasting in burn-injured mice, indicating the potential for microglial modulation in injury recovery (ref: Chen doi.org/10.1002/jcsm.13755/). In the context of COVID-19, studies have linked microglial dysfunction to systemic inflammation, highlighting the need for targeted interventions to restore microglial function and mitigate neurological complications (ref: Fekete doi.org/10.1038/s41593-025-01871-z/). These findings underscore the critical role of microglia in both neuroinflammatory responses and therapeutic interventions, paving the way for future research aimed at developing microglia-targeted therapies.