Microglia play a crucial role in the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Kaji et al. demonstrated that apolipoprotein E (APOE) aggregation in microglia initiates Aβ amyloidosis, a key event in AD pathology, by influencing lipid metabolism and the JAK/STAT signaling pathway (ref: Kaji doi.org/10.1016/j.immuni.2024.09.014/). This finding suggests that microglial uptake of APOE aggregates can trigger the formation of Aβ plaques, highlighting the importance of microglial function in AD onset. In a related study, Ross et al. explored the role of microglia and monocyte-derived macrophages in pediatric high-grade gliomas, revealing that these myeloid cells are shaped by tumor-specific histone mutations and are the predominant non-neoplastic cell population infiltrating the tumors (ref: Ross doi.org/10.1016/j.immuni.2024.09.007/). This underscores the diverse roles of microglia in different neurological contexts, particularly in tumor progression. Furthermore, Tuddenham et al. utilized single-cell RNA sequencing to identify microglial subsets associated with various neurological diseases, revealing a divide between oxidative and heterocyclic metabolism, which may inform targeted therapeutic strategies (ref: Tuddenham doi.org/10.1038/s41593-024-01764-7/). Together, these studies illustrate the multifaceted roles of microglia in neurodegenerative diseases, emphasizing their potential as therapeutic targets.

Microglial activation and inflammation are central to the progression of various neurological disorders. Hasavci et al. highlighted the essential role of the complement protein C1q in cognitive functions, demonstrating that its absence impairs fear memory extinction in mice (ref: Hasavci doi.org/10.1038/s41392-024-01989-9/). This finding suggests that microglial activation, mediated by complement signaling, is critical for certain cognitive processes. In the context of PD, Bayati et al. developed a model to study the effects of α-synuclein fibrils and proinflammatory cytokines on dopaminergic neurons, indicating that immune dysfunction may contribute to PD pathology (ref: Bayati doi.org/10.1038/s41593-024-01775-4/). Additionally, Xie et al. demonstrated that repetitive transcranial magnetic stimulation (rTMS) significantly alleviates motor impairment in PD patients, correlating with changes in peripheral inflammatory regulatory T-cells (ref: Xie doi.org/10.1186/s13024-024-00770-4/). These findings collectively emphasize the importance of microglial activation in both cognitive functions and neurodegenerative disease progression, suggesting that targeting microglial pathways could offer therapeutic benefits.

Microglia are integral to brain development and repair mechanisms, particularly following injury. Nath et al. investigated the interaction between subventricular zone microglia and neural stem cells (NSCs) in a mouse model of cortical ischemic stroke, revealing that microglial clusters negatively impact the neurogenic response, thereby limiting repair (ref: Nath doi.org/10.1038/s41467-024-53217-1/). This study highlights the dual role of microglia as both facilitators and inhibitors of neurogenesis, depending on the context. Wu et al. further elucidated the protective role of microglia in preventing degeneration of injured axons in the spinal cord, demonstrating their direct contact with myelinated axons (ref: Wu doi.org/10.1038/s41467-024-53218-0/). These findings underscore the necessity of understanding microglial functions in both developmental and pathological contexts to enhance therapeutic strategies for brain repair. Additionally, Zhang et al. explored the effects of intravenous chaperone treatment in an AD mouse model, showing that it affects amyloid plaque load and reactive gliosis, further emphasizing the potential of targeting microglial responses in therapeutic interventions (ref: Zhang doi.org/10.1038/s41398-024-03161-x/).

The interaction between microglia and other cell types is crucial for understanding their role in both health and disease. Chen et al. examined how proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage in the prenatal human brain, revealing that microglia interact with nascent vasculature in an age-dependent manner (ref: Chen doi.org/10.1038/s41593-024-01769-2/). This study highlights the importance of microglial interactions in vascular development and pathology. In the context of glioblastoma, Liu et al. demonstrated that dual targeting of macrophages and microglia can enhance therapeutic efficacy, suggesting that these immune cells play a critical role in tumor progression and therapy resistance (ref: Liu doi.org/10.1172/JCI178628/). Furthermore, the findings from Xie et al. on rTMS treatment in PD patients indicate that microglial interactions with peripheral immune cells can influence motor function recovery (ref: Xie doi.org/10.1186/s13024-024-00770-4/). Collectively, these studies emphasize the complex interplay between microglia and other cell types, which is essential for both normal physiological processes and the progression of neurological diseases.

Emerging therapeutic approaches targeting microglia hold promise for treating various neurological disorders. Qian et al. developed a microenvironment self-adaptive nanomedicine that promotes spinal cord repair by suppressing inflammation and neural apoptosis, demonstrating its potential in enhancing drug delivery and functional recovery (ref: Qian doi.org/10.1002/adma.202307624/). This innovative approach highlights the importance of targeting microglial responses in spinal cord injury. Additionally, Xie et al. reported that rTMS significantly alleviates motor impairment in PD patients, suggesting that non-invasive stimulation techniques can modulate microglial activity and improve clinical outcomes (ref: Xie doi.org/10.1186/s13024-024-00770-4/). Furthermore, Nath et al. emphasized the potential of targeting microglial interactions with NSCs to enhance neurogenic responses following stroke, indicating that therapeutic strategies could focus on modulating these interactions to promote repair (ref: Nath doi.org/10.1038/s41467-024-53217-1/). These studies collectively underscore the potential of targeting microglial mechanisms as a therapeutic strategy for various neurological conditions.

Microglial mechanisms are pivotal in the progression of various diseases, particularly in cancer and neurodegenerative disorders. Ross et al. demonstrated that microglia and monocyte-derived macrophages are key drivers of pediatric high-grade gliomas, shaped by tumor-specific histone mutations (ref: Ross doi.org/10.1016/j.immuni.2024.09.007/). This finding highlights the role of microglial activation in tumor progression and the potential for targeting these cells in glioma therapy. In the context of AD, Kaji et al. revealed that APOE aggregation in microglia initiates Aβ amyloidosis, suggesting that microglial lipid metabolism is crucial in the disease's onset (ref: Kaji doi.org/10.1016/j.immuni.2024.09.014/). Additionally, Hasavci et al. found that C1q deficiency impairs cognitive functions, indicating that microglial signaling is essential for maintaining cognitive health (ref: Hasavci doi.org/10.1038/s41392-024-01989-9/). These studies collectively emphasize the critical role of microglial mechanisms in disease progression, suggesting that targeting these pathways could offer new therapeutic avenues.

Microglial responses to environmental factors are crucial for understanding their role in health and disease. Kaji et al. explored how APOE aggregation in microglia can initiate Aβ amyloidosis, highlighting the influence of environmental factors on microglial function and AD pathology (ref: Kaji doi.org/10.1016/j.immuni.2024.09.014/). This study underscores the importance of microglial responses to lipid metabolism and environmental cues in the progression of neurodegenerative diseases. Xie et al. demonstrated that rTMS can alleviate motor impairment in PD patients, suggesting that environmental interventions can modulate microglial activity and improve clinical outcomes (ref: Xie doi.org/10.1186/s13024-024-00770-4/). Furthermore, Wang et al. investigated the role of exosomal double-stranded RNA-TLR3 signaling in morphine tolerance and hyperalgesia, indicating that microglial responses to environmental stressors can significantly impact pain pathways (ref: Wang doi.org/10.1016/j.xcrm.2024.101782/). These findings collectively highlight the dynamic nature of microglial responses to environmental factors and their implications for therapeutic strategies.

Genetic and epigenetic regulation of microglia is critical for understanding their diverse roles in health and disease. Ross et al. identified that histone mutations shape the transcriptional landscape of microglia and monocyte-derived macrophages in pediatric high-grade gliomas, suggesting that genetic factors can influence microglial behavior in tumors (ref: Ross doi.org/10.1016/j.immuni.2024.09.007/). This highlights the importance of understanding genetic regulation in microglial function. Kaji et al. further emphasized the role of microglial lipid metabolism in AD pathology, suggesting that genetic predispositions, such as APOE genotype, can influence microglial responses and disease progression (ref: Kaji doi.org/10.1016/j.immuni.2024.09.014/). Additionally, Xie et al. demonstrated that rTMS can modulate microglial activity in PD, indicating that environmental factors can interact with genetic predispositions to influence microglial function and therapeutic outcomes (ref: Xie doi.org/10.1186/s13024-024-00770-4/). These studies collectively underscore the significance of genetic and epigenetic regulation in shaping microglial responses and their implications for therapeutic strategies.