Recent studies have highlighted the critical role of microglia in Alzheimer's disease (AD), particularly their function in neuroinflammation and synaptic maintenance. For instance, the deletion of IL-34 in excitatory neurons was shown to reduce microglial numbers and TMEM119 expression, leading to increased aberrant phagocytosis of synapses in the anterior cingulate cortex (Devlin, doi.org/10.1016/j.immuni.2025.06.002/). This suggests that IL-34 is essential for maintaining proper microglial function during cortical development. Additionally, research has uncovered distinct microglial states in relation to amyloid-beta (Aβ) plaques, indicating that spatial heterogeneity among microglia may influence their contributions to AD pathology (Ardura-Fabregat, doi.org/10.1038/s41593-025-02006-0/). The identification of specific microglial proteomic profiles in human brains further emphasizes the need for tailored therapeutic strategies targeting these diverse microglial states (Mrdjen, doi.org/10.1038/s41590-025-02203-w/). Moreover, the role of G-protein-coupled receptor ADGRG1 has been elucidated, showing its involvement in driving protective microglial states through MYC activation, which may offer insights into potential therapeutic targets for AD (Zhu, doi.org/10.1016/j.neuron.2025.06.020/). The SEMA6D-TREM2 signaling pathway has also been implicated in regulating microglial function, particularly in the context of neuron-microglia cross-talk near Aβ plaques (D'Oliveira Albanus, doi.org/10.1126/scitranslmed.adx0027/). These findings collectively underscore the complex interplay between microglial activation, synaptic integrity, and neuroinflammation in AD, paving the way for future research into microglial-targeted therapies.

The genetic landscape influencing microglial activation in Alzheimer's disease has been further elucidated through various studies. Notably, TET2-mutant myeloid cells were found to mitigate AD progression by enhancing phagocytosis and infiltrating the central nervous system, demonstrating a protective role against late-onset AD (Matatall, doi.org/10.1016/j.stem.2025.06.006/). This suggests that specific genetic mutations can confer resilience against neurodegenerative processes. Additionally, a multi-omics approach has revealed how genetic variants in brain vascular cells contribute to disease risk, highlighting the importance of vascular health in neurodegenerative diseases (Reid, doi.org/10.1016/j.neuron.2025.07.001/). The STING pathway has been identified as a key regulator of neuroinflammation, with its activation leading to non-inflammatory neurodegeneration in conditions like NGLY1 deficiency (Yang, doi.org/10.1084/jem.20242296/). Furthermore, the interplay between microglial signaling and metabolic changes, particularly in relation to triglyceride metabolism and APOE4 genotype, has been shown to influence microglial phenotypes and inflammatory responses (Stephenson, doi.org/10.1016/j.celrep.2025.115961/). These findings emphasize the multifaceted genetic and molecular mechanisms that govern microglial activation and their implications for neurodegenerative disease progression.

Microglia play a significant role in various neurodegenerative diseases beyond Alzheimer's, particularly in amyotrophic lateral sclerosis (ALS) and glioblastoma. A recent study utilizing single-cell transcriptomics revealed a predominant undifferentiated microglial phenotype in the ALS brain, characterized by dysregulated respiratory electron transport, which may contribute to disease progression (Tuddenham, doi.org/10.1007/s00401-025-02913-3/). This highlights the potential for developing targeted therapies aimed at specific microglial responses in ALS. In glioblastoma, innovative approaches such as the in vivo generation of CAR macrophages using enucleated mesenchymal stem cells have shown promise in reprogramming glioma-associated microglia/macrophages for therapeutic purposes (Zhou, doi.org/10.1073/pnas.2426724122/). Additionally, the role of neuroinflammation in Parkinson's disease has been underscored by findings that activated TBK1 promotes microglial lipid droplet accumulation, exacerbating neuroinflammation and dopaminergic neuron death (Han, doi.org/10.1186/s12974-025-03517-0/). These studies collectively illustrate the diverse roles of microglia across different neurodegenerative conditions and the potential for microglial-targeted therapies to mitigate disease progression.

Microglial interactions with other cell types are crucial for understanding their role in neuroinflammation and disease progression. For instance, a study demonstrated that the deletion of microglial C3ar1 attenuated stress-induced social behavior deficits, indicating that microglial signaling significantly influences synaptic and behavioral outcomes under chronic stress conditions (Tripathi, doi.org/10.1038/s41380-025-03097-8/). This highlights the importance of microglial signaling pathways in mediating interactions with neurons and their impact on behavior. In retinitis pigmentosa, dual-targeting of CSF1R signaling was shown to attenuate neurotoxic myeloid activation, preserving photoreceptors and suggesting that microglial activation can be modulated to protect against retinal degeneration (Wu, doi.org/10.1186/s12974-025-03525-0/). Furthermore, glycoprotein NMB was identified as a key mediator of bidirectional interactions between glioblastoma stem cells and tumor-associated macrophages, emphasizing the complexity of microglial interactions within the tumor microenvironment (Liu, doi.org/10.1172/jci.insight.187684/). These findings underscore the multifaceted roles of microglia in mediating cross-talk with other cell types, which can have significant implications for therapeutic strategies.

Microglia are increasingly recognized for their responses to environmental factors, which can influence neuroinflammation and neurodegenerative processes. A study investigating the effects of non-biogenic nanoparticles on developing mice found that microglia phagocytose these particles through a complement-dependent mechanism, suggesting a protective role against environmental neurotoxicity (Ogaki, doi.org/10.1186/s12974-025-03475-7/). This highlights the importance of understanding how environmental exposures can impact microglial function and brain health. Additionally, research into sepsis-associated encephalopathy revealed that pharmacological inhibition of the cGAS-STING pathway can suppress microglial pyroptosis, indicating potential therapeutic targets for managing neuroinflammation in sepsis (Zeng, doi.org/10.1186/s12974-025-03507-2/). Furthermore, liver-specific expression of ANGPTL8 was shown to promote AD progression by activating microglial pyroptosis, linking systemic factors to local neuroinflammatory responses (Wei, doi.org/10.1186/s12974-025-03487-3/). These studies collectively emphasize the intricate relationship between environmental factors and microglial responses, which can significantly influence neurodegenerative disease outcomes.

Emerging therapeutic strategies targeting microglial activity are showing promise in the context of neurodegenerative diseases. A multi-ancestry genome-wide meta-analysis identified novel risk loci for Alzheimer's disease, providing insights into genetic factors that could be targeted for therapeutic interventions (Rajabli, doi.org/10.1186/s13059-025-03564-z/). Additionally, the in vivo generation of CAR macrophages for glioblastoma therapy demonstrates a novel approach to reprogramming microglia/macrophages, potentially enhancing therapeutic efficacy against aggressive tumors (Zhou, doi.org/10.1073/pnas.2426724122/). Moreover, a wearable ultrasonic device designed for continuous amyloid-beta disaggregation presents a non-invasive method to address AD pathology, highlighting the potential for innovative technologies in therapeutic strategies (Zou, doi.org/10.1126/sciadv.adw1732/). Natural compounds like magnoflorine have also been identified for their dual therapeutic effects on colitis and anxiety, showcasing the potential of targeting microglial-mediated neuroinflammation in various contexts (Wang, doi.org/10.1186/s40168-025-02158-y/). These findings underscore the importance of developing targeted therapies that modulate microglial activity to improve outcomes in neurodegenerative diseases.

The dynamics of microglia across the lifespan are crucial for understanding their role in neurodegenerative diseases. Using two-photon live imaging, researchers have shown that microglia exhibit distinct behaviors during physiological and injury-induced conditions, with responses to injuries being uncoordinated and delayed (Tieu, doi.org/10.1016/j.celrep.2025.115991/). This suggests that aging may impair microglial responsiveness, potentially contributing to neurodegenerative processes. Furthermore, the activation of type I interferon signaling has been implicated in worsening autoimmunity in neuromyelitis optica spectrum disorder, indicating that age-related changes in immune signaling pathways may exacerbate disease severity (Zhang, doi.org/10.1002/advs.202500942/). Additionally, alterations in triglyceride metabolism have been linked to microglial phenotypes associated with the APOE4 genotype, further illustrating how aging and metabolic changes can influence microglial function and inflammatory responses (Stephenson, doi.org/10.1016/j.celrep.2025.115961/). These studies collectively highlight the importance of understanding microglial dynamics and aging in the context of neurodegenerative diseases.

The relationship between microglial activity and behavioral outcomes is an emerging area of research, particularly concerning the effects of environmental exposures. For instance, gestational cannabis exposure has been shown to affect social behavior and microglial activation in the developing amygdala, suggesting that prenatal exposures can have lasting impacts on neurodevelopment (Pham, doi.org/10.1038/s41386-025-02173-5/). This underscores the importance of understanding how early-life exposures can shape microglial function and subsequent behavioral outcomes. Moreover, chronic alcohol consumption has been linked to alterations in microglial phenotypes, resulting in a hyper-inflammatory state that may contribute to cognitive decline and increased risk for neurodegenerative diseases (Hemati, doi.org/10.1016/j.bbi.2025.07.022/). Additionally, studies have shown that prenatal alcohol exposure induces microglia to release exosomes that participate in neuronal apoptosis, further illustrating the role of microglia in mediating stress responses and behavioral changes (Tarale, doi.org/10.1016/j.bbi.2025.07.016/). These findings highlight the critical role of microglia in linking environmental factors to behavioral outcomes, emphasizing the need for further research in this area.