Microglia, the resident immune cells of the central nervous system, play a crucial role in neuroinflammation and neurodegenerative diseases. Recent studies have highlighted the impact of genetic variants on microglial function, particularly the APOE-Christchurch variant, which has been shown to suppress microglial cGAS-STING responses, thereby enhancing the clearance of pathological tau aggregates in Alzheimer's disease models (ref: Akay doi.org/10.1016/j.immuni.2025.07.019/). Furthermore, transcriptional profiling of ex vivo human microglia has revealed significant changes associated with Alzheimer's disease phenotypes, indicating dysregulation in gene expression and coexpression modules that correlate with disease severity (ref: Kosoy doi.org/10.1038/s41593-025-02020-2/). The interplay between microglia and other glial cells, such as astrocytes, is also critical; microglia have been shown to regulate neuronal activity through structural remodeling of astrocytes, which is essential for maintaining synaptic transmission (ref: Gu doi.org/10.1016/j.neuron.2025.07.024/). Additionally, the role of dopaminergic signaling in modulating microglial activity during adolescence suggests that microglial responses are not only crucial in pathological states but also in normal developmental processes (ref: Stowell doi.org/10.1038/s41467-025-63314-4/). Overall, these findings underscore the multifaceted roles of microglia in both neuroinflammatory responses and neurodevelopmental processes, highlighting their potential as therapeutic targets in neurodegenerative diseases.

Microglia are increasingly recognized for their pivotal role in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Recent research has demonstrated that β-amyloid induces microglial expression of Glypican 4 (GPC4) and APOE, which exacerbates neuronal tau pathology and toxicity, suggesting a detrimental feedback loop in Alzheimer's pathology (ref: Holmes doi.org/10.1186/s13024-025-00883-4/). In Parkinson's disease, LRRK2 kinase activity has been shown to regulate lysosomal lipid levels, with pathogenic variants leading to increased kinase activity that affects lipid metabolism critical for neuronal health (ref: Maloney doi.org/10.1186/s13024-025-00880-7/). Furthermore, single-nucleus transcriptomics has revealed a distinct microglial state across dementia subtypes, with increased MSR1-mediated phagocytosis being a common feature, indicating that microglial activation patterns may serve as biomarkers for disease progression (ref: Chia doi.org/10.1186/s13073-025-01519-4/). The therapeutic potential of early intervention with anti-Aβ immunotherapy has also been highlighted, showing that it can attenuate microglial activation without inducing exhaustion, thereby preserving their function in plaque clearance (ref: de Weerd doi.org/10.1186/s13024-025-00878-1/). Collectively, these studies illustrate the complex interactions between microglia and neurodegenerative processes, emphasizing the need for targeted therapeutic strategies that modulate microglial function.

Microglial responses to injury are critical for tissue repair and recovery following central nervous system damage. Recent studies have explored innovative therapeutic approaches, such as localized delivery of interleukin-13 via hydrogels, which has shown promise in enhancing recovery in spinal cord injury models by promoting alternative immune activation (ref: Walsh doi.org/10.1016/j.bioactmat.2025.07.018/). Additionally, the use of small extracellular vesicles from young blood has been investigated for their potential to treat endothelial senescence, highlighting the role of microglial communication in systemic inflammation and recovery (ref: Hu doi.org/10.1002/adma.202418352/). The interplay between microglia and other cell types, such as astrocytes and neurons, is crucial for effective repair mechanisms; for instance, dopaminergic signaling has been shown to regulate microglial surveillance during critical developmental periods (ref: Stowell doi.org/10.1038/s41467-025-63314-4/). Furthermore, the development of injectable hydrogels that modulate reactive oxygen species and inhibit microglial ferroptosis presents a novel strategy for alleviating neuropathic pain and promoting spinal cord injury repair (ref: Li doi.org/10.1016/j.redox.2025.103816/). These findings underscore the importance of understanding microglial responses in injury contexts to develop effective therapeutic interventions.

The genetic and molecular underpinnings of microglial activation are critical for understanding their role in neurodegenerative diseases. Recent findings have identified the histone demethylase PHF2 as a key regulator of inflammatory genes in Alzheimer's disease, with significant upregulation observed in both human postmortem tissues and mouse models (ref: Yang doi.org/10.1038/s41380-025-03181-z/). This suggests that epigenetic modifications play a crucial role in modulating microglial responses to neuroinflammation. Additionally, the knockdown of USP22 has been shown to alleviate LPS-induced microglial inflammation and associated depressive-like behaviors, indicating that specific molecular pathways can be targeted to mitigate microglial activation (ref: Lu doi.org/10.1038/s41386-025-02207-y/). The development of a potent TREM2 agonistic antibody further highlights the potential for targeting microglial receptors to enhance their protective functions in neurodegenerative contexts (ref: da Silva Almeida doi.org/10.1080/19420862.2025.2546554/). Furthermore, meta-analysis of differentially expressed genes across neurodegenerative datasets has revealed insights into the reproducibility of findings, emphasizing the need for robust methodologies in studying microglial activation (ref: Nakatsuka doi.org/10.1038/s41467-025-62579-z/). These studies collectively contribute to a deeper understanding of the genetic and molecular mechanisms that govern microglial activation and their implications for therapeutic strategies.

Microglial interactions with other cell types are essential for maintaining brain homeostasis and responding to injury. Recent research has shown that microglia can influence neuronal health through various mechanisms, including the modulation of synaptic pruning processes. For instance, studies have demonstrated that microglial depletion in models of prenatal and postnatal immune activation leads to significant behavioral and electrophysiological changes, underscoring the importance of microglial-neuronal interactions in neurodevelopmental outcomes (ref: Ciano Albanese doi.org/10.1016/j.bbi.2025.07.018/). Additionally, the localized delivery of interleukin-13 has been shown to improve functional recovery in spinal cord injury models, highlighting the role of microglia in mediating immune responses and tissue repair (ref: Walsh doi.org/10.1016/j.bioactmat.2025.07.018/). The interplay between microglia and astrocytes is also critical; dopaminergic signaling has been found to regulate microglial surveillance during adolescence, suggesting that these interactions are vital for cognitive development (ref: Stowell doi.org/10.1038/s41467-025-63314-4/). Furthermore, the therapeutic potential of targeting microglial receptors, such as TREM2, indicates that enhancing microglial interactions with other cell types could be a promising strategy for treating neurodegenerative diseases (ref: da Silva Almeida doi.org/10.1080/19420862.2025.2546554/). These findings emphasize the complexity of microglial interactions within the brain and their implications for health and disease.

Emerging therapeutic strategies targeting microglia are gaining attention for their potential to mitigate neuroinflammation and promote recovery in neurodegenerative diseases. One promising approach involves the localized delivery of interleukin-13, which has been shown to enhance functional and histopathological recovery in spinal cord injury models, suggesting that immunomodulatory therapies can effectively harness microglial responses for repair (ref: Walsh doi.org/10.1016/j.bioactmat.2025.07.018/). Additionally, the antidepressant effects of a peptide derived from the sea cucumber Apostichopus japonicus have been linked to its ability to modulate inflammatory pathways, highlighting the potential for anti-inflammatory agents in treating mood disorders associated with microglial activation (ref: Zhuo doi.org/10.1016/j.freeradbiomed.2025.08.031/). Furthermore, the development of TREM2 agonistic antibodies represents a novel strategy to enhance microglial function in Alzheimer's disease, as TREM2 is crucial for microglial activation and response to amyloid pathology (ref: da Silva Almeida doi.org/10.1080/19420862.2025.2546554/). These therapeutic approaches underscore the importance of targeting microglial pathways to develop effective treatments for neurodegenerative diseases, emphasizing the need for continued research into the mechanisms underlying microglial activation and function.

The relationship between microglial function and behavioral outcomes is a growing area of research, particularly in the context of neurodevelopmental and psychiatric disorders. Studies have shown that microglial depletion during critical periods of development can lead to significant behavioral and electrophysiological alterations, suggesting that microglial activity is essential for normal brain function and resilience to stress (ref: Ciano Albanese doi.org/10.1016/j.bbi.2025.07.018/). Additionally, social hierarchy and individual resilience have been linked to stress-induced PTSD, with microglial inflammation playing a key role in mediating these effects (ref: Gou doi.org/10.1038/s41380-025-03171-1/). The histone demethylase PHF2 has also been implicated in regulating inflammatory genes associated with cognitive impairment in Alzheimer's disease, further connecting microglial activity to behavioral outcomes (ref: Yang doi.org/10.1038/s41380-025-03181-z/). Furthermore, the development of therapeutic strategies targeting microglial pathways, such as TREM2 agonists, highlights the potential for modulating microglial function to improve behavioral outcomes in neurodegenerative and psychiatric disorders (ref: da Silva Almeida doi.org/10.1080/19420862.2025.2546554/). These findings underscore the critical role of microglia in shaping behavioral responses and the potential for therapeutic interventions aimed at modulating microglial activity.