Microglial activation plays a crucial role in the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease (AD). A study demonstrated that histone H4 lysine 12 lactylation enhances microglial glucose metabolism, promoting a shift from oxidative phosphorylation to glycolysis, which exacerbates AD pathology. Inhibition of this lactylation cycle in microglia reduced amyloid-beta (Aβ) burden and cognitive deficits in a mouse model of AD (ref: Pan doi.org/10.1016/j.cmet.2022.02.013/). Additionally, large extracellular vesicles released by activated microglia were found to propagate early synaptic dysfunction in AD, suggesting a novel mechanism for the disease's progression (ref: Gabrielli doi.org/10.1093/brain/). Furthermore, Aβ oligomers were shown to trigger necroptosis in neurons via microglial activation, linking microglial responses to neurodegeneration (ref: Salvadores doi.org/10.1186/s40478-022-01332-9/). Contradictory findings emerged regarding the effects of environmental factors, such as ozone exposure, which impaired microglial function and exacerbated Aβ plaque load, indicating that external stressors can significantly influence microglial behavior (ref: Greve doi.org/10.1093/brain/). Overall, these studies highlight the complex interplay between microglial activation, neuroinflammation, and neurodegenerative processes, emphasizing the need for targeted therapeutic strategies.

Microglia exhibit region-specific heterogeneity and play pivotal roles in neurodegenerative diseases. Research has characterized distinct microglial subtypes in the developing human brain, revealing their dynamic transitions and regional specifications that are crucial for brain development and disease pathogenesis (ref: Li doi.org/10.1016/j.stem.2022.02.004/). In the context of Alzheimer's disease, the role of chronic neuroinflammation has been proposed as a driving factor for synaptic and neuronal loss, with studies suggesting that targeting neuroinflammatory pathways may mitigate cognitive decline (ref: Lecca doi.org/10.1002/alz.12610/). Additionally, the expression of chitinase-3-like protein 1 (CHI3L1) has been implicated in neuroinflammation and AD, although its precise mechanisms remain unclear (ref: Connolly doi.org/10.1002/alz.12612/). In Parkinson's disease, altered expression of the CD200-CD200R1 inhibitory pathway was observed, indicating that microglial activation may contribute to disease progression (ref: Rabaneda-Lombarte doi.org/10.1038/s41531-022-00290-2/). These findings underscore the importance of understanding microglial functions and their interactions with neuronal populations in the context of neurodegenerative diseases.

Microglia are essential for brain development, particularly in synaptic pruning and the maturation of neural circuits. A study demonstrated that microglia's ability to prune synapses is dependent on phosphatidylserine exposure, highlighting their role in the functional maturation of adult-born neurons (ref: Kurematsu doi.org/10.1084/jem.20202304/). Furthermore, early-life stress was shown to impair microglial pruning of excitatory synapses, leading to aberrant stress responses in adulthood, suggesting that microglial dysfunction during critical developmental windows can have lasting effects on brain function (ref: Bolton doi.org/10.1016/j.celrep.2022.110600/). Additionally, the communication between neurons and astrocytes, mediated by NMDA receptor signaling, was found to regulate astrocyte proliferation during brain development, indicating a complex interplay between different glial cell types (ref: Zhou doi.org/10.1016/j.celrep.2022.110557/). These studies collectively illustrate the multifaceted roles of microglia in shaping neural circuits and their potential implications for neurodevelopmental disorders.

Microglial interactions with other cell types are critical for maintaining brain homeostasis and responding to injury. Research has shown that microglia regulate chandelier cell axo-axonic synaptogenesis, which is vital for controlling neuronal firing and network output (ref: Gallo doi.org/10.1073/pnas.2114476119/). Additionally, the cross-talk between GABAergic postsynapses and microglia was found to influence synapse loss following brain ischemia, indicating that microglial activation can modulate synaptic plasticity in pathological conditions (ref: Cramer doi.org/10.1126/sciadv.abj0112/). The role of CSF-1 in maintaining pathogenic microglial populations during autoimmune neuroinflammation was also highlighted, suggesting that targeting specific microglial subsets could be a therapeutic strategy (ref: Hwang doi.org/10.1073/pnas.2111804119/). These findings emphasize the importance of microglial interactions with neurons and other glial cells in both health and disease, revealing potential avenues for therapeutic intervention.

Environmental factors significantly influence microglial activation and function, impacting neuroinflammation and neurodegeneration. A Mendelian randomization study indicated that inflammation could lead to structural brain changes through microglial activation in various neuropsychiatric disorders (ref: Williams doi.org/10.1001/jamapsychiatry.2022.0407/). Furthermore, the effects of ozone exposure on microglial behavior were explored, revealing that it impairs microglial ability to form protective barriers around Aβ plaques, exacerbating neurodegenerative processes (ref: Greve doi.org/10.1093/brain/). Additionally, early-life adversity was shown to disrupt microglial pruning of excitatory synapses, leading to altered stress responses in adulthood (ref: Bolton doi.org/10.1016/j.celrep.2022.110600/). These studies highlight the critical role of environmental factors in modulating microglial responses and their implications for neurodevelopmental and neurodegenerative diseases.

Emerging therapeutic strategies targeting microglial function hold promise for treating neurodegenerative diseases. A study developed metformin-based supramolecular nanodrugs that enhance microglial clearance of Aβ, demonstrating a synergistic effect when combined with donepezil (ref: Fan doi.org/10.1016/j.biomaterials.2022.121452/). Additionally, baseline microglial activation was found to correlate with brain amyloidosis and cognitive decline in Alzheimer's disease, suggesting that modulating microglial activity could be a viable therapeutic approach (ref: Wang doi.org/10.1212/NXI.0000000000001152/). Furthermore, the adenosine A2A receptor was shown to suppress astrocyte-mediated inflammation, indicating that targeting glial signaling pathways may mitigate neuroinflammatory processes (ref: Yuan doi.org/10.3389/fimmu.2022.841290/). These findings underscore the potential of developing targeted therapies that modulate microglial activity to improve outcomes in neurodegenerative conditions.

Microglial heterogeneity and their phenotypic variations are critical for understanding their roles in health and disease. Research has demonstrated that microglia exhibit strain-specific responses to lipopolysaccharide (LPS) exposure, with significant differences in MHC-I pathway regulation observed between different mouse strains (ref: Piirsalu doi.org/10.3390/cells11061032/). Additionally, the activation of the RARα receptor was shown to attenuate neuroinflammation after subarachnoid hemorrhage, highlighting the potential for targeting specific microglial phenotypes in therapeutic strategies (ref: Tian doi.org/10.3389/fimmu.2022.839796/). Furthermore, the role of ER-mitochondria communication in NLRP3 inflammasome activation in microglia under stress conditions was explored, revealing the complex molecular interactions that govern microglial responses (ref: Pereira doi.org/10.1007/s00018-022-04211-7/). These studies emphasize the importance of understanding microglial heterogeneity to develop targeted interventions for various neurological disorders.

Microglia play a pivotal role in the development and maintenance of pain and neuropathic conditions. A study found that activation of the NLRP3 inflammasome in motoneurons following sciatic nerve injury leads to excessive neuroinflammation and impedes regeneration, suggesting that targeting this pathway could enhance recovery after nerve injury (ref: Molnár doi.org/10.1186/s12974-022-02427-9/). Additionally, strain-specific differences in neuroinflammation were observed in response to LPS, indicating that genetic background can influence microglial activation and subsequent pain responses (ref: Piirsalu doi.org/10.3390/cells11061032/). Furthermore, the modulation of microglial polarization in diabetic retinopathy was linked to altered A20 expression, which negatively regulates M1 polarization, suggesting that therapeutic strategies aimed at microglial polarization could be beneficial in managing neuropathic pain (ref: Chen doi.org/10.3389/fimmu.2022.813979/). These findings highlight the critical role of microglia in pain mechanisms and their potential as therapeutic targets in neuropathic conditions.