Microglial activation plays a pivotal role in neuroinflammation, particularly in the context of neurodegenerative diseases such as Alzheimer's disease (AD). A study involving 130 individuals demonstrated that microglial activation and tau accumulation propagate together across Braak stages, suggesting a colocalization of these processes in the living human brain (ref: Pascoal doi.org/10.1038/s41591-021-01456-w/). Another investigation highlighted the significance of formyl peptide receptor 1 (FPR1) in amplifying inflammatory brain injury following intracerebral hemorrhage (ICH), identifying it as a key damage-associated molecular pattern receptor predominantly expressed by microglia (ref: Li doi.org/10.1126/scitranslmed.abe9890/). Furthermore, TREM2-dependent lipid droplet biogenesis in microglia was shown to be crucial for remyelination, indicating that microglial responses to myelin debris are essential for resolving inflammation and promoting repair (ref: Gouna doi.org/10.1084/jem.20210227/). The interplay between microglia and other cell types, such as astrocytes and neurons, is also critical, as demonstrated by the effects of astrocyte-derived TNF and glutamate on microglial activation in response to methamphetamine (ref: Canedo doi.org/10.1038/s41386-021-01139-7/). Additionally, environmental factors such as cognitive stimulation can modulate microglial activation, with reduced levels of CCL11/eotaxin mediating the beneficial effects of environmental enrichment on cognitive decline in aging (ref: Scabia doi.org/10.1016/j.bbi.2021.08.222/).

Microglia are increasingly recognized for their dual role in neurodegenerative diseases, acting both as protectors and contributors to pathology. A phase 2b trial of tolebrutinib, a brain-penetrant BTK inhibitor, demonstrated its efficacy in reducing active brain lesions in relapsing multiple sclerosis, highlighting the potential for targeting microglial pathways in treatment (ref: Reich doi.org/10.1016/S1474-4422(21)00237-4/). In Alzheimer's disease, the acute phase protein lactoferrin was identified as a key feature that predicts amyloid-beta burden, suggesting that persistent neuroinflammation may exacerbate AD pathology (ref: Tsatsanis doi.org/10.1038/s41380-021-01248-1/). Moreover, genetically predicted brain C4A expression was associated with microglial activation and altered hippocampal morphology, linking immune system alterations to schizophrenia and neurodegeneration (ref: Da Silva doi.org/10.1016/j.biopsych.2021.06.021/). The role of microglia in white matter pathology was further emphasized in studies showing that lysosomal dysfunction in microglia contributes to TDP-43 proteinopathy in frontotemporal dementia (ref: Wu doi.org/10.1016/j.celrep.2021.109581/). These findings underscore the complex interactions between microglia and neurodegenerative processes, suggesting that therapeutic strategies targeting microglial function may hold promise for mitigating disease progression.

Microglia are essential for brain repair and regeneration, particularly following injury. Research has shown that microglial modulation can enhance recovery after ischemic stroke, with regulatory T cells directing microglial repair processes to support oligodendrogenesis and improve white matter integrity (ref: Zera doi.org/10.1016/j.tins.2021.07.005/). Additionally, erythropoietin has been found to promote neurodifferentiation and microglial involvement in the adult hippocampus, indicating a regulatory feedback loop that enhances cognitive performance under stress (ref: Fernandez Garcia-Agudo doi.org/10.1016/j.celrep.2021.109548/). The impact of microglial activation on functional recovery was further illustrated in studies utilizing two-photon imaging to observe the neuroinflammatory response to intracortical implants, revealing that microglial morphology can be significantly altered post-implantation (ref: Yang doi.org/10.1016/j.biomaterials.2021.121060/). Moreover, maternal diet was shown to influence microglial activation and neurogenesis in offspring, suggesting that early environmental factors can shape microglial responses and brain development (ref: Xavier doi.org/10.1016/j.bbi.2021.08.223/). These findings highlight the critical role of microglia in both the maintenance of brain homeostasis and the facilitation of recovery following injury.

Microglia are integral to synaptic plasticity, influencing both neuroinflammation and neuronal health. Studies have demonstrated that microglial activation can modulate synaptic function and plasticity, particularly in response to neuroinflammatory signals. For instance, the activation of neuroprotective microglia and astrocytes at lesion sites has been shown to be crucial for spontaneous locomotor recovery after spinal cord injury, indicating their role in facilitating synaptic repair (ref: Kisucká doi.org/10.3390/cells10081943/). Additionally, the differential responses of Müller cells and microglia in retinal detachment models have provided insights into how these cells interact and contribute to synaptic health in the retina (ref: Lee doi.org/10.3390/cells10081972/). Furthermore, the use of machine learning approaches to analyze cerebrospinal fluid proteomics in Alzheimer's disease has revealed potential biomarkers of neuroinflammation that correlate with synaptic dysfunction (ref: Gaetani doi.org/10.3390/cells10081930/). These studies collectively underscore the importance of microglial function in maintaining synaptic integrity and facilitating plasticity in both healthy and pathological states.

Microglia play a critical role in the pathophysiology of stroke and ischemia, influencing both injury outcomes and recovery processes. Research has shown that inhibiting P2X4 receptors can attenuate white matter injury following intracerebral hemorrhage by promoting a shift from pro-inflammatory to anti-inflammatory microglial phenotypes, thereby enhancing neurofunctional recovery (ref: Fu doi.org/10.1186/s12974-021-02239-3/). Additionally, the upregulation of neuronal chemokine-like factor 1 (CKLF1) in the ischemic penumbra has been linked to microglial polarization, suggesting that microglial responses to neuronal signals are crucial in determining stroke outcomes (ref: Zhou doi.org/10.1038/s41401-021-00746-w/). The development of a neurovascular unit-on-a-chip has further advanced our understanding of microglial interactions with other cell types in the context of ischemic stroke, providing a platform for evaluating stem cell therapies (ref: Lyu doi.org/10.1038/s41551-021-00744-7/). These findings highlight the multifaceted roles of microglia in stroke pathology and recovery, emphasizing their potential as therapeutic targets.

Environmental factors significantly influence microglial activation and function, impacting neuroinflammation and cognitive health. Exercise has been shown to protect against hippocampal inflammation and neurodegeneration in models of multiple sclerosis, suggesting that physical activity can modulate microglial responses and promote neuroprotection (ref: Rizzo doi.org/10.1016/j.bbi.2021.08.212/). Similarly, maternal diet before and during pregnancy has been found to modulate microglial activation and neurogenesis in postpartum rats, indicating that early-life environmental conditions can shape microglial behavior and brain development (ref: Xavier doi.org/10.1016/j.bbi.2021.08.223/). Furthermore, reduced levels of CCL11/eotaxin have been implicated in the beneficial effects of environmental enrichment on cognitive performance in aging, highlighting the role of microglial modulation in response to enriched environments (ref: Scabia doi.org/10.1016/j.bbi.2021.08.222/). These studies underscore the dynamic interplay between environmental factors and microglial function, suggesting that lifestyle interventions may offer therapeutic avenues for enhancing brain health.

Microglia are central to immune modulation within the central nervous system, influencing both neuroinflammatory responses and neurodegenerative processes. The development of a neurovascular unit-on-a-chip has facilitated the evaluation of stem cell therapies for ischemic stroke, revealing how microglial interactions with other cell types can modulate therapeutic outcomes (ref: Lyu doi.org/10.1038/s41551-021-00744-7/). In the context of multiple sclerosis, the oral BTK inhibitor tolebrutinib demonstrated a dose-dependent reduction in MRI lesions, highlighting the potential for targeting microglial pathways to ameliorate disease (ref: Reich doi.org/10.1016/S1474-4422(21)00237-4/). Additionally, the association of genetically predicted C4A expression with microglial markers and hippocampal morphology suggests that immune system alterations can impact neurodevelopment and psychiatric conditions (ref: Da Silva doi.org/10.1016/j.biopsych.2021.06.021/). The acute phase protein lactoferrin has also been identified as a key feature in Alzheimer's disease, linking neuroinflammation to amyloid-beta pathology (ref: Tsatsanis doi.org/10.1038/s41380-021-01248-1/). Collectively, these findings emphasize the critical role of microglia in immune modulation and their potential as therapeutic targets in various neurological disorders.