Microglial cells play a pivotal role in the central nervous system (CNS), particularly in the context of neuroinflammation and the clearance of nanoparticles. Gao et al. demonstrated that microglial extracellular vesicles (EVs) are crucial for the clearance of both organic and inorganic nanoparticles from the brain, highlighting the modulatory role of these EVs in determining the fate of nanoparticles within the CNS (ref: Gao doi.org/10.1038/s41565-023-01551-8/). In the context of Alzheimer's disease (AD), Millet et al. and Tagliatti et al. explored how the APOE4 allele and aging influence microglial states. They identified an exhausted-like microglial population that accumulates in aged and APOE4 genotype AD brains, characterized by inflammatory signals and stress markers (ref: Millet doi.org/10.1016/j.immuni.2023.12.001/; Tagliatti doi.org/10.1016/j.immuni.2023.12.002/). Furthermore, Berglund et al. revealed that an autophagy-dependent microglial population emerges in aging mice, suggesting that microglia can adopt protective roles against neurodegenerative processes (ref: Berglund doi.org/10.1038/s41467-023-44556-6/). Together, these studies underscore the dual role of microglia in both promoting and mitigating neuroinflammation, depending on the context and specific microglial states involved.

Microglia are increasingly recognized for their role in neurodegenerative diseases, particularly Alzheimer's and Parkinson's diseases. In studies by Millet et al. and Li et al., the interaction between aging, APOE4 genotype, and microglial function was examined, revealing a conserved exhausted-like microglial state that is enriched in elderly and APOE4 AD brains (ref: Millet doi.org/10.1016/j.immuni.2023.12.001/; Li doi.org/10.1016/j.immuni.2023.12.015/). This state is characterized by increased inflammatory signaling and stress markers, suggesting that aging and genetic predisposition significantly alter microglial behavior in AD. Additionally, Martirosyan et al. focused on Parkinson's disease, investigating the loss of dopaminergic neurons and the role of aggregated α-synuclein, which is critical for understanding the disease's pathology (ref: Martirosyan doi.org/10.1186/s13024-023-00699-0/). The findings emphasize the need for targeted therapies that address the unique microglial responses in these neurodegenerative contexts, as well as the potential for microglial modulation to alter disease progression.

The activation of microglia is a double-edged sword in the context of CNS injury and repair. Gao et al. developed a targeted mRNA nanoparticle approach to modulate microglial polarization post-ischemic stroke, demonstrating that M2 microglia can ameliorate blood-brain barrier disruption and promote recovery (ref: Gao doi.org/10.1021/acsnano.3c09817/). This study highlights the therapeutic potential of manipulating microglial states to enhance recovery after CNS injuries. Similarly, Garcia-Bonilla et al. conducted a single-cell transcriptomic analysis of brain and blood cells following ischemic stroke, revealing the dynamic changes in immune cell populations that contribute to both injury and repair (ref: Garcia-Bonilla doi.org/10.1038/s41590-023-01711-x/). Furthermore, Peshoff et al. explored the role of TREM2 in glioblastoma, finding that it regulates phagocytosis and influences tumor progression, thus linking microglial activation to cancer biology (ref: Peshoff doi.org/10.1093/neuonc/). Collectively, these studies illustrate the complex interplay between microglial activation, neuroinflammation, and tissue repair mechanisms in the CNS.

Microglia are integral to the immune response in the CNS, particularly in the context of neurodegenerative diseases and stress responses. Li et al. examined how APOE4 and aging influence microglial states in Alzheimer's disease, identifying a conserved exhausted-like microglial state that is enriched in elderly brains (ref: Li doi.org/10.1016/j.immuni.2023.12.015/). This finding underscores the impact of genetic and age-related factors on microglial function and their role in disease progression. Chen et al. further investigated the role of microglia in anxiety-related behaviors following acute stress, revealing that microglial activation in the ventral hippocampus is crucial for the extinction of anxiety-like behaviors (ref: Chen doi.org/10.1038/s41467-024-44704-6/). Additionally, the study by Lv et al. highlighted the dysregulation of adenosine signaling in glial cells, linking microglial activation to pain-related anxiodepression (ref: Lv doi.org/10.1016/j.bbi.2024.01.012/). These studies collectively emphasize the multifaceted roles of microglia in modulating immune responses and their implications for neuropsychiatric conditions.

The aging process significantly influences microglial function and their role in disease progression. Millet et al. and Li et al. explored the interplay between aging, APOE4 genotype, and microglial activation in Alzheimer's disease, identifying a reactive microglial population that accumulates with age and genetic predisposition (ref: Millet doi.org/10.1016/j.immuni.2023.12.001/; Li doi.org/10.1016/j.immuni.2023.12.015/). This population exhibits a unique transcriptomic profile characterized by inflammatory signals, suggesting that aging exacerbates neuroinflammatory responses. Berglund et al. further contributed to this theme by demonstrating that an autophagy-dependent microglial population emerges in aging mice, which may protect against neurodegenerative processes (ref: Berglund doi.org/10.1038/s41467-023-44556-6/). Additionally, Gao et al. developed a targeted mRNA nanoparticle approach to modulate microglial polarization post-stroke, indicating that therapeutic strategies aimed at microglial modulation could be beneficial in age-related neurodegenerative diseases (ref: Gao doi.org/10.1021/acsnano.3c09817/). These findings highlight the critical role of microglia in mediating the effects of aging on neurodegenerative disease progression.

Therapeutic strategies targeting microglia are gaining attention for their potential to modulate neuroinflammation and improve outcomes in various CNS disorders. Gao et al. developed a novel mRNA nanoparticle approach aimed at selectively delivering therapeutic agents to M2 microglia, demonstrating its efficacy in ameliorating blood-brain barrier disruption following ischemic stroke (ref: Gao doi.org/10.1021/acsnano.3c09817/). This innovative strategy highlights the potential for targeted therapies to harness the beneficial aspects of microglial activation while mitigating harmful inflammatory responses. Additionally, Peshoff et al. investigated the role of TREM2 in glioblastoma, revealing that TREM2 signaling regulates phagocytosis and could serve as a therapeutic target to enhance immune responses against tumors (ref: Peshoff doi.org/10.1093/neuonc/). Furthermore, Wang et al. identified palmitoylation of PKCδ in hypothalamic microglia as a potential therapeutic target for fatty liver disease, illustrating the diverse roles of microglia in metabolic regulation (ref: Wang doi.org/10.7150/thno.89602/). These studies underscore the importance of developing targeted therapies that modulate microglial function to address a range of neurological and metabolic disorders.

Microglia are essential for proper neurodevelopment and play a critical role in maintaining neuronal health. Gao et al. demonstrated that microglial extracellular vesicles (EVs) are vital for the clearance of nanoparticles from the brain, suggesting that microglial function is crucial for maintaining homeostasis during development (ref: Gao doi.org/10.1038/s41565-023-01551-8/). Furthermore, Tagliatti et al. highlighted the importance of TREM2 in regulating the bioenergetic profile of developing neurons, indicating that microglial signaling can influence neuronal development and metabolic fitness (ref: Tagliatti doi.org/10.1016/j.immuni.2023.12.002/). The studies by Millet et al. and Li et al. also contribute to this theme by examining how aging and genetic factors, such as the APOE4 allele, affect microglial states in Alzheimer's disease, revealing that these factors can lead to the accumulation of reactive microglial populations that may disrupt normal neurodevelopmental processes (ref: Millet doi.org/10.1016/j.immuni.2023.12.001/; Li doi.org/10.1016/j.immuni.2023.12.015/). Collectively, these findings underscore the critical role of microglia in neurodevelopment and their potential impact on neurodegenerative disease progression.