Microglial activation plays a crucial role in neuroinflammation, particularly following brain injuries such as repetitive mild closed head injury (rmCHI). A study demonstrated that cognitive impairments associated with rmCHI are linked to significant alterations in local immune cell recruitment, especially the activation of microglia, which showed upregulation of complement receptors and phagocytic proteins (ref: Mallah doi.org/10.1038/s41392-025-02466-7/). Additionally, RNA sequencing and proteomic analyses indicated that pathways related to neurodegeneration and neuronal apoptosis were significantly altered in rmCHI models. Another study identified a specific microglial subtype expressing the C5a receptor 1 (C5aR1) in human cerebral edema tissue, suggesting that microglial heterogeneity complicates therapeutic targeting in conditions like stroke and traumatic brain injury (ref: Zhou doi.org/10.1016/j.neuron.2025.10.022/). These findings highlight the complex interplay between microglial activation and neuroinflammatory responses in various neurological conditions, emphasizing the need for targeted therapeutic approaches to modulate microglial activity effectively. In the context of Alzheimer's disease (AD), microglia have been shown to influence astrocyte reactivity, which is critical for understanding the disease's progression. Research indicated that activated microglia can induce reactive astrogliosis in AD, with a study examining 101 individuals revealing a significant association between microglial activation and amyloid-beta (Aβ) deposition (ref: Ferrari-Souza doi.org/10.1038/s41593-025-02103-0/). Furthermore, therapeutic strategies targeting microglial functions, such as the anti-Aβ antibody Lecanemab, have been shown to activate microglial effector functions, leading to reduced Aβ pathology and neuritic damage in a human microglia xenograft mouse model (ref: Albertini doi.org/10.1038/s41593-025-02125-8/). These studies collectively underscore the pivotal role of microglial activation in neuroinflammatory processes and their implications for therapeutic interventions in neurodegenerative diseases.

Microglia are increasingly recognized as key players in the pathophysiology of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Friedreich's Ataxia (FRDA). In AD, microglial dysfunction is linked to impaired autophagy, which is a hallmark of the disease. A study demonstrated that both macroautophagy and chaperone-mediated autophagy pathways are disrupted in AD model mice, preceding β-amyloid accumulation and driving disease progression (ref: Li doi.org/10.1038/s41392-025-02453-y/). This disruption is compounded by the challenges posed by the blood-brain barrier, which limits therapeutic modulation of these pathways. Additionally, microglia have been shown to modulate astrocyte reactivity in AD, with evidence suggesting that activated microglia can induce reactive astrogliosis, further complicating the disease's progression (ref: Ferrari-Souza doi.org/10.1038/s41593-025-02103-0/). In the context of FRDA, research utilizing patient-derived induced pluripotent stem cells revealed an intrinsic microglial phenotype characterized by mitochondrial defects and iron overload, suggesting that microglial inflammation may act as a primary mediator of neuronal death in this condition (ref: Pernaci doi.org/10.1038/s41467-025-66710-y/). Furthermore, genetic factors such as a trisomy 21-associated gene variant have been identified as protective against AD, highlighting the potential for genetic resilience in microglial function (ref: Jin doi.org/10.1038/s41593-025-02117-8/). These findings emphasize the dual role of microglia as both contributors to neurodegeneration and potential targets for therapeutic intervention, underscoring the complexity of their involvement in neurodegenerative diseases.

Cognitive impairment is closely linked to microglial activation, particularly in the context of repetitive mild closed head injury (rmCHI) and neurodegenerative diseases. A study found that cognitive deficits following rmCHI were associated with significant alterations in immune cell recruitment, particularly the activation of microglia, which exhibited upregulation of complement receptors and phagocytic proteins (ref: Mallah doi.org/10.1038/s41392-025-02466-7/). This suggests that microglial activation plays a critical role in the cognitive outcomes of individuals suffering from rmCHI. Furthermore, the therapeutic potential of modulating microglial activity is highlighted by the use of Lecanemab, an anti-Aβ antibody that activates microglial functions to clear amyloid pathology, thereby improving cognitive outcomes in AD models (ref: Albertini doi.org/10.1038/s41593-025-02125-8/). In addition to direct effects on cognition, microglia also influence astrocyte reactivity, which is crucial for maintaining neuronal health. Research has shown that activated microglia can induce reactive astrogliosis, further exacerbating cognitive decline in AD (ref: Ferrari-Souza doi.org/10.1038/s41593-025-02103-0/). The interplay between microglial activation and cognitive impairment underscores the importance of understanding microglial mechanisms in the development of therapeutic strategies aimed at mitigating cognitive decline in neurodegenerative diseases.

Microglia play a vital role in the brain's response to injury and subsequent repair processes. Following spinal cord injury (SCI), reactive astrocytes and microglia work in concert to facilitate neural repair. A study highlighted the importance of glial spatial organization, demonstrating that reactive astrocytes extend processes to corral the lesion core and sequester debris, while microglia contribute to maintaining tissue homeostasis (ref: Ni doi.org/10.1038/s41467-025-65095-2/). This coordinated response is essential for guiding axon pathfinding across lesion sites, indicating that microglial and astrocytic interactions are crucial for effective neural repair. Furthermore, research utilizing advanced imaging techniques has shown that microglia actively sustain tissue viscoelasticity, which is critical for cellular behavior in the brain (ref: So doi.org/10.1002/adma.202517493/). This mechanical homeostasis is disrupted in various pathological conditions, suggesting that targeting microglial functions may enhance recovery following brain injuries. Additionally, studies have indicated that microglial activation can influence synaptic pruning, with differential selectivity observed between microglia and astrocytes in models of HIV-1-induced synaptic pruning (ref: Watson doi.org/10.1093/brain/). These findings collectively underscore the multifaceted roles of microglia in injury response and repair, highlighting their potential as therapeutic targets in neurotrauma and neurodegenerative conditions.

Genetic and epigenetic factors significantly influence microglial function and their responses to neurodegenerative diseases. A notable study identified a myeloid trisomy 21-associated gene variant that appears to confer resilience against Alzheimer's disease (AD), suggesting that specific genetic variations can modulate microglial activity and protect against neurodegeneration (ref: Jin doi.org/10.1038/s41593-025-02117-8/). This finding highlights the potential for genetic predispositions to shape microglial responses and offers insights into the mechanisms underlying resilience in certain populations, such as individuals with Down syndrome. Additionally, research examining the TMEM106B gene has revealed its role in altering microglial activation and cytokine responses in chronic traumatic encephalopathy (CTE). The presence of the TMEM106B risk genotype was associated with increased CTE stage and higher odds of TDP-43 inclusions, indicating that genetic variations can significantly impact microglial behavior in response to neurodegenerative pathology (ref: Hartman doi.org/10.1007/s00401-025-02955-7/). These studies underscore the importance of understanding the genetic and epigenetic landscape of microglia, as it may provide novel avenues for therapeutic interventions aimed at modulating microglial functions in various neurological disorders.

Microglial interactions with other cell types, particularly astrocytes and neurons, are crucial for maintaining brain homeostasis and responding to pathological conditions. In Alzheimer's disease (AD), activated microglia have been shown to modulate astrocyte reactivity, which is essential for understanding the disease's progression. A study involving positron emission tomography radiotracers demonstrated a significant association between microglial activation and amyloid-beta (Aβ) deposition, indicating that microglia can influence astrocytic responses in the context of AD (ref: Ferrari-Souza doi.org/10.1038/s41593-025-02103-0/). This interaction is further complicated by the role of microglia in synaptic pruning, where differential selectivity between microglia and astrocytes has been observed in models of HIV-1-induced synaptic alterations (ref: Watson doi.org/10.1093/brain/). Moreover, microglia-derived nanovesicles have been implicated in synchronizing macroautophagy and chaperone-mediated autophagy for therapeutic purposes in AD, highlighting the potential for microglial-derived factors to influence neuronal health and disease progression (ref: Li doi.org/10.1038/s41392-025-02453-y/). These findings emphasize the importance of microglial interactions with other cell types in the brain, as they play a pivotal role in both normal physiology and the pathogenesis of neurodegenerative diseases.

Therapeutic strategies targeting microglia are gaining attention as potential interventions for neurodegenerative diseases. One prominent approach involves the use of Lecanemab, an anti-amyloid antibody that activates microglial effector functions to mediate amyloid clearance in Alzheimer's disease (AD). Research demonstrated that Lecanemab significantly reduces Aβ pathology and associated neuritic damage in a human microglia xenograft mouse model, suggesting that enhancing microglial activity can lead to improved outcomes in AD (ref: Albertini doi.org/10.1038/s41593-025-02125-8/). This highlights the therapeutic potential of modulating microglial functions to combat neurodegeneration. Additionally, genetic factors influencing microglial resilience, such as a trisomy 21-associated gene variant, have been identified as protective against AD, indicating that understanding genetic predispositions can inform therapeutic strategies (ref: Jin doi.org/10.1038/s41593-025-02117-8/). Furthermore, the role of microglia in mediating synaptic pruning and their interactions with astrocytes present additional avenues for therapeutic exploration. For instance, differential selectivity in synaptic pruning activity between microglia and astrocytes has been observed in models of HIV-1-induced synaptic alterations, suggesting that targeting these interactions may enhance therapeutic efficacy (ref: Watson doi.org/10.1093/brain/). Collectively, these studies underscore the importance of developing targeted therapies that harness the beneficial aspects of microglial functions while mitigating their potentially harmful effects in neurodegenerative diseases.

Microglial responses to environmental and metabolic changes are critical for maintaining brain health and responding to injury. A study on repetitive mild closed head injury (rmCHI) revealed that cognitive impairments were associated with significant alterations in local immune cell recruitment, particularly the activation of microglia, which exhibited upregulation of complement receptors and phagocytic proteins (ref: Mallah doi.org/10.1038/s41392-025-02466-7/). This indicates that microglia are sensitive to environmental changes and play a pivotal role in the neuroinflammatory response following injury. Additionally, the study highlighted major changes in pathways associated with neurodegeneration and neuronal apoptosis, emphasizing the need for targeted interventions to modulate microglial activity in response to such changes. Moreover, research has shown that microglia-derived nanovesicles can synchronize macroautophagy and chaperone-mediated autophagy, which are crucial for cellular homeostasis, particularly in Alzheimer's disease (ref: Li doi.org/10.1038/s41392-025-02453-y/). The ability of microglia to adapt to metabolic changes and influence autophagic processes underscores their importance in maintaining neuronal health. Furthermore, genetic variations, such as those in the TMEM106B gene, have been linked to altered microglial activation and cytokine responses in chronic traumatic encephalopathy (CTE), suggesting that genetic predispositions can shape microglial responses to environmental stressors (ref: Hartman doi.org/10.1007/s00401-025-02955-7/). These findings collectively highlight the dynamic nature of microglial responses to environmental and metabolic changes, emphasizing their potential as therapeutic targets in neurodegenerative diseases.