Microglia play a crucial role in neurodegenerative diseases, particularly in Alzheimer's disease (AD) and frontotemporal dementia (FTD). In a study utilizing high-throughput mass cytometry on the 5×FAD mouse model, researchers identified senescent microglia expressing TREM2, a gene associated with AD risk, which exhibited a distinct signature from disease-associated microglia (DAM) (ref: Rachmian doi.org/10.1038/s41593-024-01620-8/). Another investigation into FTD revealed that osteopontin drives neuroinflammation and cell loss in patient neurons, highlighting the complex mechanisms leading to neurodegeneration (ref: Al-Dalahmah doi.org/10.1016/j.stem.2024.03.013/). Furthermore, antibody-mediated targeting of the inhibitory receptor LILRB4 on microglia was shown to attenuate amyloid pathology in AD models, suggesting that modulating microglial activity could be a therapeutic strategy (ref: Hou doi.org/10.1126/scitranslmed.adj9052/). The clinicopathologic heterogeneity in AD was examined using the corticolimbic index, revealing diverse glial activation patterns among individuals (ref: Kouri doi.org/10.1001/jamaneurol.2024.0784/). Additionally, the regulation of microglial gene expression through RNAase-H active antisense oligonucleotides demonstrated potential for modifying microglial responses to amyloid plaques in vivo (ref: Vandermeulen doi.org/10.1186/s13024-024-00725-9/). These findings collectively underscore the multifaceted roles of microglia in neurodegenerative processes and their potential as therapeutic targets.

Microglial activation is a pivotal component of neuroinflammation, with significant implications for various neurological disorders. In FTD, osteopontin was found to drive neuroinflammation and neuronal cell loss, indicating a critical role for microglial activation in disease progression (ref: Al-Dalahmah doi.org/10.1016/j.stem.2024.03.013/). The study of LILRB4 in microglia revealed that its targeting could mitigate amyloid pathology in AD, emphasizing the balance between activating and inhibitory signals in microglial function (ref: Hou doi.org/10.1126/scitranslmed.adj9052/). The heterogeneity of glial activation patterns in AD was further explored through the FLAME cohort, which highlighted the variability in neuroimaging and clinicopathologic characteristics among patients (ref: Kouri doi.org/10.1001/jamaneurol.2024.0784/). Moreover, the role of type 2 cannabinoid receptors in regulating neuroinflammation during graft-versus-host disease was elucidated, showcasing the intricate interplay between immune signaling and microglial activation (ref: Moe doi.org/10.1172/JCI175205/). The characterization of microglial phenotypic states in glioblastoma revealed their transition to diverse functional states, which are crucial for tumor growth and response to therapies (ref: Yabo doi.org/10.1186/s13073-024-01321-8/). Collectively, these studies illustrate the complex dynamics of microglial activation and its implications for neuroinflammatory conditions.

Microglia are increasingly recognized for their roles in the tumor microenvironment, particularly in glioblastoma (GBM). Research has shown that GBM-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features, which are essential for tumor growth and treatment response (ref: Yabo doi.org/10.1186/s13073-024-01321-8/). Enhancing glioblastoma immunotherapy through the re-education of tumor-associated microglia and macrophages has emerged as a promising strategy, with integrated chimeric antigen receptor T cells showing superior efficacy in GBM treatment (ref: Zhu doi.org/10.1021/acsnano.4c00050/). Additionally, blocking the MIF-CD74 axis was found to augment radiotherapy efficacy for brain metastasis in non-small cell lung cancer by promoting microglia M1 polarization, highlighting the potential for targeted therapies in modulating the tumor microenvironment (ref: Liu doi.org/10.1186/s13046-024-03024-9/). The interaction between high-fat diet-induced metabolic syndrome and microglial activation also underscores the influence of systemic factors on tumor progression and microglial function (ref: Liu doi.org/10.1186/s12974-024-03097-5/). These findings collectively emphasize the critical role of microglia in cancer biology and their potential as therapeutic targets.

Microglia are integral to cognitive function and behavior, with emerging evidence linking their activity to various neuropsychiatric conditions. A study demonstrated that nuclear GAPDH in cortical microglia mediates stress-induced cognitive inflexibility, suggesting a molecular mechanism underlying cognitive deficits (ref: Ramos doi.org/10.1038/s41380-024-02553-1/). Furthermore, the role of microglial type I interferon signaling in brain development was highlighted, indicating that microglia contribute to the clearance of unwanted neurons, which is crucial for proper neural plasticity (ref: Baker doi.org/10.1016/j.it.2024.04.004/). Research on P2RY12 deficiency revealed sex-specific microglial perturbations and behavioral anomalies, emphasizing the importance of considering sex differences in microglial research (ref: Uweru doi.org/10.1186/s12974-024-03079-7/). Additionally, the destabilization of fear memory through Rac1-driven communication between engram cells and microglia illustrates the complex interactions that influence memory processes (ref: Chen doi.org/10.1016/j.bbi.2024.04.024/). These studies collectively underscore the multifaceted roles of microglia in cognitive function and their potential impact on neuropsychiatric disorders.

Microglia respond dynamically to environmental factors, influencing neurobehavioral outcomes and neuroinflammation. A study found that high-fat diet consumption leads to adolescent neurobehavioral abnormalities and hippocampal structural alterations via microglial overactivation, highlighting the impact of diet on brain health (ref: Yao doi.org/10.1016/j.bbi.2024.04.005/). Additionally, the role of fascin-1 in limiting myosin activity in microglia was explored, demonstrating its importance in controlling the mechanical properties of the injured spinal cord (ref: Huang doi.org/10.1186/s12974-024-03089-5/). Research on interleukin-6 knockout mice indicated that this cytokine is crucial for developing learning and memory deficits in a model of neuropsychiatric lupus, further linking environmental factors to microglial responses (ref: Reynolds doi.org/10.1186/s12974-024-03085-9/). Moreover, TREM2 was shown to alleviate white matter injury after traumatic brain injury, mediated by microglial regulation, emphasizing the protective roles microglia can play in response to environmental stressors (ref: Li doi.org/10.1002/ctm2.1665/). These findings illustrate the significant influence of environmental factors on microglial behavior and their implications for neuroinflammatory conditions.

The interactions between microglia and the immune system are critical for understanding neuroinflammation and neurodegeneration. Research has shown that nigrostriatal degeneration influences glial inflammatory and phagocytic activity, indicating that microglial responses are context-dependent and crucial for neurodegenerative disease progression (ref: Ayerra doi.org/10.1186/s12974-024-03091-x/). The role of fascin-1 in microglial function was further elucidated, demonstrating its importance in regulating mechanical properties of the glial scar following spinal cord injury (ref: Huang doi.org/10.1186/s12974-024-03089-5/). Additionally, NRF2 activation was found to ameliorate cognitive impairment and NLRP3 inflammasome activation in microglia following chronic alcohol exposure, suggesting potential therapeutic avenues for neuroinflammation (ref: Lin doi.org/10.1016/j.freeradbiomed.2024.04.236/). The immunomodulatory effects of human umbilical cord blood mesenchymal stem cells on microglial activation and anxiety-like behavior in a maternal immune activation model of schizophrenia further highlight the interplay between microglia and the immune system (ref: Cui doi.org/10.1016/j.pnpbp.2024.111010/). Collectively, these studies emphasize the critical role of microglia in mediating immune responses within the central nervous system.

Microglial mechanisms are central to the processes of neuroinflammation, with various studies elucidating their roles in different contexts. The identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease models highlights their potential contribution to neuroinflammatory processes (ref: Rachmian doi.org/10.1038/s41593-024-01620-8/). Osteopontin's role in driving neuroinflammation and cell loss in frontotemporal dementia underscores the complexity of microglial involvement in neurodegenerative diseases (ref: Al-Dalahmah doi.org/10.1016/j.stem.2024.03.013/). The targeting of LILRB4 on microglia has been shown to attenuate amyloid pathology, indicating that modulating specific receptors can influence neuroinflammatory outcomes (ref: Hou doi.org/10.1126/scitranslmed.adj9052/). Furthermore, the study of glial activation patterns in Alzheimer's disease revealed significant heterogeneity, suggesting that individual differences in microglial responses may affect disease progression (ref: Kouri doi.org/10.1001/jamaneurol.2024.0784/). The regulation of microglial gene expression through antisense oligonucleotides presents a novel approach to modifying their inflammatory responses in vivo (ref: Vandermeulen doi.org/10.1186/s13024-024-00725-9/). These findings collectively highlight the intricate mechanisms by which microglia contribute to neuroinflammation and their potential as therapeutic targets.