Microglial dysfunction has been increasingly recognized as a contributing factor in neurodegenerative diseases, particularly Alzheimer's disease (AD). A pivotal study demonstrated that TREM2, a receptor expressed on microglia, signals through PLCG2 to mediate essential functions such as cell survival, phagocytosis, and lipid metabolism in human microglia (ref: Andreone doi.org/10.1038/s41593-020-0650-6/). This finding underscores the importance of TREM2 in maintaining microglial health and its potential role in AD pathology. Additionally, research has shown that NAD+ regeneration is crucial for brain health, with a mouse model indicating that mitochondrial complex I activity supports organismal survival through NAD+ regeneration, while its bioenergetic function is vital for motor control (ref: McElroy doi.org/10.1016/j.cmet.2020.06.003/). Furthermore, studies on neuromyelitis optica (NMO) have revealed that microglia play a complementary role to astrocytes in the disease's pathology, with microglial activation contributing to astrocyte loss and demyelination (ref: Moinfar doi.org/10.1172/JCI138804/; ref: Chen doi.org/10.1172/JCI134816/). These findings collectively highlight the multifaceted roles of microglia in neurodegenerative diseases, emphasizing their potential as therapeutic targets.

Microglial activation is a critical component of the inflammatory response in various neurological conditions. For instance, a study found that the loss of the small GTPase Rhoa in microglia leads to spontaneous activation, resulting in neurodegeneration characterized by synapse loss and memory deficits (ref: Socodato doi.org/10.1016/j.celrep.2020.107796/). This suggests that Rhoa is essential for maintaining microglial quiescence and neuronal health. Additionally, research has shown that T cell engagement with microglia can protect the brain from viral infections, indicating a complex interplay between adaptive and innate immune responses (ref: Moseman doi.org/10.1126/sciimmunol.abb1817/). Moreover, serum IgG from children with opsoclonus-myoclonus syndrome was found to induce microglial activation, enhancing neuronal cytolysis through the NO/sGC/PKG pathway (ref: Ding doi.org/10.1186/s12974-020-01839-9/). These studies illustrate the dual role of microglia in both protective and detrimental inflammatory processes, highlighting their potential as targets for therapeutic intervention in neuroinflammatory diseases.

Microglia play a significant role in the tumor microenvironment, particularly in glioblastoma (GBM). Research has identified junctional adhesion molecule A (JAM-A) as a potential tumor suppressor in female microglia, suggesting that its expression may influence tumor growth and patient prognosis (ref: Turaga doi.org/10.1093/neuonc/). Additionally, tumor-associated microglia/macrophages (TAM) have been shown to promote glioblastoma through mTOR-mediated immunosuppression, indicating that GBM-initiating cells can induce mTOR signaling specifically in microglia (ref: Dumas doi.org/10.15252/embj.2019103790/). Furthermore, the interaction between microglia and extracellular vesicles has been implicated in facilitating tumor growth, highlighting the complex dynamics of microglial involvement in cancer (ref: Wang doi.org/10.7150/thno.45688/). These findings underscore the importance of understanding microglial functions in the context of cancer, as they may offer novel therapeutic avenues for targeting tumor progression.

The interactions between microglia and other glial cells are crucial for maintaining central nervous system (CNS) homeostasis and responding to injury. In neuromyelitis optica (NMO), microglia were found to complement astrocytes in the disease process, with microglial activation contributing to astrocyte loss and subsequent demyelination (ref: Moinfar doi.org/10.1172/JCI138804/). Additionally, a study highlighted the physical interaction between microglia and astrocytes, driven by complement signaling, which plays a critical role in the evolving lesions of NMO (ref: Chen doi.org/10.1172/JCI134816/). These interactions are not only pivotal in pathological conditions but also in protective responses, as demonstrated by the ability of microglia to engage with T cells to thwart viral infections (ref: Moseman doi.org/10.1126/sciimmunol.abb1817/). Collectively, these studies emphasize the importance of microglial interactions with astrocytes and other glial cells in both health and disease, suggesting that targeting these interactions may provide therapeutic benefits.

Microglial responses to injury are critical for CNS repair mechanisms. Following traumatic brain injury (TBI), microglia can exhibit both protective and detrimental effects. For instance, a study demonstrated that enhancing M2-like macrophage populations post-TBI did not lead to improved functional outcomes, indicating that simply increasing these populations may not be sufficient for effective repair (ref: Enam doi.org/10.1186/s12974-020-01860-y/). Additionally, hypertonic saline treatment was shown to alleviate blood-brain barrier permeability and reduce infarct volume by modulating microglial activation through the NLRP3 inflammasome (ref: Wang doi.org/10.1111/cns.13427/). Furthermore, ethyl pyruvate has been identified as a potential therapeutic agent for sepsis-associated encephalopathy by inhibiting the NLRP3 inflammasome, highlighting the role of microglia in inflammatory responses following injury (ref: Zhong doi.org/10.1186/s10020-020-00181-3/). These findings illustrate the complex role of microglia in injury responses and underscore the potential for therapeutic strategies aimed at modulating their activity to enhance repair mechanisms.

Microglia serve as a critical interface between the immune system and the CNS, influencing both neuroinflammatory responses and neurodegenerative processes. Research has shown that TREM2 signaling in microglia is essential for mediating inflammatory responses and maintaining cellular homeostasis in Alzheimer's disease (ref: Andreone doi.org/10.1038/s41593-020-0650-6/). Additionally, the engagement of T cells with microglia has been found to protect the brain from viral infections, highlighting the role of microglia in orchestrating immune responses (ref: Moseman doi.org/10.1126/sciimmunol.abb1817/). Furthermore, serum IgG-induced microglial activation has been linked to enhanced neuronal cytolysis, suggesting that microglia can exacerbate neuroinflammatory conditions (ref: Ding doi.org/10.1186/s12974-020-01839-9/). These interactions underscore the dual role of microglia in both protective and pathogenic processes, emphasizing their potential as therapeutic targets in various neurological disorders.

Microglia are increasingly recognized for their role in metabolic disorders, particularly in the context of Alzheimer's disease and metabolic syndrome. A study demonstrated that metabolic syndrome exacerbates amyloid pathology in a comorbid Alzheimer's mouse model, suggesting that metabolic dysfunction can influence neurodegenerative processes (ref: Tyagi doi.org/10.1016/j.bbadis.2020.165849/). Additionally, the characterization of TNF and IL-1 systems in the human brain post-ischemic stroke revealed increased expression in glial cells, indicating that metabolic stress can trigger inflammatory responses in the CNS (ref: Clausen doi.org/10.1186/s40478-020-00957-y/). Furthermore, microglial activation induced by serum IgG in children with opsoclonus-myoclonus syndrome highlights the impact of systemic metabolic factors on microglial function and neuronal health (ref: Ding doi.org/10.1186/s12974-020-01839-9/). These findings suggest that targeting microglial responses in the context of metabolic disorders may offer new therapeutic strategies for mitigating neurodegenerative diseases.

Therapeutic strategies aimed at modulating microglial function are gaining attention in the treatment of neurodegenerative diseases. One promising approach involves the use of IFN-γ to restore microglial autophagy, which has been shown to promote amyloid-β clearance and improve cognitive function in Alzheimer's disease models (ref: He doi.org/10.1038/s41419-020-2644-4/). Additionally, the activation of the Nrf2 pathway through novel compounds has been explored as a means to protect dopaminergic neurons from degeneration (ref: Lee doi.org/10.1016/j.expneurol.2020.113387/). Furthermore, the characterization of TNF and IL-1 systems in the brain after ischemic stroke has revealed potential targets for therapeutic intervention aimed at reducing neuroinflammation (ref: Clausen doi.org/10.1186/s40478-020-00957-y/). These studies highlight the potential of targeting microglial pathways to develop effective treatments for various neurological disorders, emphasizing the need for further research in this area.