Microglial cells play a crucial role in the pathophysiology of neurodegenerative diseases, particularly in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Recent studies have highlighted the importance of microglial interactions with neuronal components, such as the IL-33 signaling pathway, which is essential for synaptic plasticity and the engulfment of extracellular matrix (ECM) proteins by microglia. Loss of IL-33 in neurons leads to impaired microglial function and contributes to memory deficits, indicating that microglial remodeling is vital for maintaining synaptic integrity (ref: Nguyen doi.org/10.1016/j.cell.2020.05.050/). Additionally, spatial transcriptomics has revealed that microglial responses to amyloid plaques in AD involve complex gene co-expression networks, with early changes linked to myelin and oligodendrocyte genes, and later phases characterized by inflammatory responses (ref: Chen doi.org/10.1016/j.cell.2020.06.038/). The differential effects of genetic risk factors, such as APOE and TREM2, on microglial phenotypes further complicate our understanding of AD pathology, as TREM2 deficiency alters the transcriptomic landscape of microglia in the context of APOE4 (ref: Fitz doi.org/10.1186/s13024-020-00394-4/). Moreover, the role of microglia in ALS has been underscored by findings that knockout of neurotoxic factors released by microglia can significantly extend survival in ALS mouse models (ref: Guttenplan doi.org/10.1038/s41467-020-17514-9/). These studies collectively emphasize the multifaceted roles of microglia in neurodegenerative diseases, highlighting their potential as therapeutic targets.

Neuroinflammation, mediated by microglia, is a critical factor in various neurological disorders, including gliomas and Alzheimer's disease. Recent research has shown that tumor-associated macrophages (TAMs) and microglia undergo dynamic changes in response to therapies such as radiotherapy, which can alter their phenotypes and abundance, potentially influencing treatment outcomes (ref: Akkari doi.org/10.1126/scitranslmed.aaw7843/). In the context of gliomas, the emergence of immune escape clones during immunotherapy highlights the need for understanding the interactions between microglia and tumor cells (ref: Maire doi.org/10.1172/JCI138760/). Furthermore, microglial calcium signaling has been shown to be responsive to neuronal activity, suggesting that microglial activation is closely linked to synaptic function and may contribute to neuroinflammatory processes (ref: Umpierre doi.org/10.7554/eLife.56502/). In Alzheimer's disease, microglia exhibit unique transcriptional profiles that differ from those observed in mouse models, indicating that human microglial responses may be distinct and warrant further investigation (ref: Srinivasan doi.org/10.1016/j.celrep.2020.107843/). These findings underscore the complexity of microglial roles in neuroinflammation and their potential implications for therapeutic strategies.

Microglial activation is a double-edged sword in the context of neuroinflammation, with both protective and detrimental effects depending on the context and timing of their activation. For instance, the metalloprotease ADAM17 has been implicated in protective TNF signaling pathways that help mitigate age-related degeneration in the Drosophila retina, suggesting that microglial activation can have beneficial outcomes (ref: Muliyil doi.org/10.15252/embj.2020104415/). Conversely, in multiple sclerosis (MS), the failure of remyelination is linked to the stage of lesions, indicating that microglial responses can vary significantly based on the disease context (ref: Heß doi.org/10.1007/s00401-020-02189-9/). Additionally, astrocytes and microglia have been shown to coordinate their actions during neuronal corpse removal, highlighting the importance of their interactions in maintaining homeostasis in the central nervous system (ref: Damisah doi.org/10.1126/sciadv.aba3239/). The interplay between aging, sex, and microglial phagocytic activity further complicates our understanding of their immune responses, with evidence suggesting that aged female microglia exhibit enhanced phagocytosis compared to their male counterparts (ref: Yanguas-Casás doi.org/10.1111/acel.13182/). These studies illustrate the nuanced roles of microglia in immune responses and their potential as therapeutic targets in neurodegenerative diseases.

Microglia play a significant role in the tumor microenvironment, influencing cancer progression and response to therapies. Recent findings indicate that microglial activation is involved in alcohol dependence, with genomic and synaptic changes observed in the central nucleus of the amygdala of alcohol-dependent mice (ref: Warden doi.org/10.1016/j.biopsych.2020.05.011/). Additionally, the glycosyltransferase EXTL2 has been identified as a promoter of neuroinflammation following demyelination, suggesting that microglial interactions with proteoglycans can modulate inflammatory responses in the context of multiple sclerosis (ref: Pu doi.org/10.1186/s12974-020-01895-1/). In schizophrenia, microglial activation is associated with cognitive deficits and altered cytokine profiles, indicating that neuroinflammation may contribute to the pathophysiology of this disorder (ref: Murphy doi.org/10.1186/s12974-020-01890-6/). Furthermore, the role of microglia in mediating anxiety-like behavior has been demonstrated in Cyld knockout mice, linking microglial activation to behavioral outcomes (ref: Han doi.org/10.1016/j.bbi.2020.07.011/). These studies highlight the diverse roles of microglia in cancer and neuroinflammatory conditions, emphasizing their potential as therapeutic targets.

Microglial interactions with other cell types are critical for maintaining brain homeostasis and responding to injury. Recent research has elucidated the role of microglia in synaptic pruning during development, where they facilitate the elimination of excess synapses through mechanisms involving phosphatidylserine externalization (ref: Scott-Hewitt doi.org/10.15252/embj.2020105380/). This process is essential for proper neuronal circuit assembly and highlights the importance of microglial function in shaping neural networks. Additionally, microglial calcium signaling has been shown to be responsive to neuronal activity, indicating that microglia are not merely passive observers but actively participate in modulating synaptic function (ref: Umpierre doi.org/10.7554/eLife.56502/). In the context of Alzheimer's disease, the transplantation of human neurons into mouse models has provided insights into the interactions between microglia and neurons expressing different apolipoproteins, revealing how these interactions may influence disease progression (ref: Najm doi.org/10.1016/j.celrep.2020.107962/). These findings underscore the complexity of microglial interactions with other cell types and their implications for neurodevelopment and neurodegenerative diseases.

Microglia are increasingly recognized for their roles in synaptic plasticity and repair processes following injury. In Alzheimer's disease, microglial activation states, such as damage-associated microglia (DAM), have been linked to synaptic dysfunction and neurodegeneration (ref: Srinivasan doi.org/10.1016/j.celrep.2020.107843/). Studies have shown that microglia can influence the structural remodeling of synapses, which is essential for learning and memory. For instance, the knockout of factors that activate reactive astrocytes has been shown to slow disease progression in ALS models, suggesting that microglial signaling can impact astrocytic responses and, consequently, neuronal health (ref: Guttenplan doi.org/10.1038/s41467-020-17514-9/). Furthermore, morphometric analyses of microglia and astrocytes in heart failure models have revealed time-dependent changes in glial cell structure that correlate with inflammatory cytokine levels, indicating that microglial states can influence recovery and repair mechanisms in the brain (ref: Althammer doi.org/10.1186/s12974-020-01892-4/). These studies highlight the dual role of microglia in both promoting synaptic repair and contributing to neurodegenerative processes.

Microglial responses are significantly influenced by environmental and genetic factors, which can modulate their activation states and functional outcomes. For example, dietary fat has been shown to exacerbate hypothalamic inflammation, leading to glial reactivity and immune cell infiltration, suggesting that lifestyle factors can directly impact microglial function (ref: Cansell doi.org/10.1002/glia.23882/). Additionally, genetic factors such as the presence of the APOE4 allele have been linked to altered microglial responses in Alzheimer's disease, highlighting the interplay between genetics and environmental influences on neuroinflammation (ref: Najm doi.org/10.1016/j.celrep.2020.107962/). The glycosyltransferase EXTL2 has also been implicated in promoting neuroinflammation following demyelination, indicating that genetic variations can affect microglial interactions with the extracellular matrix and contribute to disease pathology (ref: Pu doi.org/10.1186/s12974-020-01895-1/). Furthermore, the knockout of the CYLD gene has been associated with anxiety-like behaviors, linking genetic factors to microglial activation and behavioral outcomes (ref: Han doi.org/10.1016/j.bbi.2020.07.011/). These findings underscore the importance of understanding how environmental and genetic factors shape microglial responses in health and disease.

Microglial mechanisms are pivotal in the progression of various neurological diseases, influencing both neuroinflammatory responses and neuronal health. In Alzheimer's disease, the unique transcriptional profiles of human microglia have been shown to differ from those in mouse models, suggesting that human-specific microglial responses may play a critical role in disease progression (ref: Srinivasan doi.org/10.1016/j.celrep.2020.107843/). Additionally, microglial calcium signaling has been linked to neuronal activity, indicating that microglial responses are not only reactive but also actively modulate synaptic plasticity and repair (ref: Umpierre doi.org/10.7554/eLife.56502/). The presence of A1 reactive astrocytes and the loss of TREM2 have been associated with early pathology in cerebral amyloid angiopathy, further emphasizing the role of microglia in the progression of neurodegenerative diseases (ref: Taylor doi.org/10.1186/s12974-020-01900-7/). Moreover, vagus nerve stimulation has been shown to reduce neuroinflammation and motor deficits in Parkinson's disease models, suggesting that modulating microglial activity through neurostimulation may offer therapeutic benefits (ref: Farrand doi.org/10.1016/j.brs.2020.06.078/). These studies collectively highlight the critical role of microglia in disease progression and their potential as therapeutic targets.