Microglia, the resident immune cells of the central nervous system, play a crucial role in neuroinflammation and neurodegenerative diseases. Recent studies have identified acetate, a microbiota-derived short-chain fatty acid, as a key regulator of microglial maturation and function. Erny et al. demonstrated that acetate enhances microglial metabolic fitness and modulates their phagocytic activity, suggesting its potential therapeutic role in neurodegenerative conditions (ref: Erny doi.org/10.1016/j.cmet.2021.10.010/). Furthermore, d'Errico et al. explored the role of microglia in the propagation of amyloid beta (Aβ) into unaffected brain regions, showing that microglial infiltration is associated with increased Aβ deposition in grafted neurons, highlighting their involvement in Alzheimer's disease pathology (ref: d'Errico doi.org/10.1038/s41593-021-00951-0/). In a different context, Wang et al. found that neuronal accumulation of peroxidated lipids activates the microglial NLRP3 inflammasome, leading to neuroinflammation and demyelination, underscoring the detrimental effects of lipid peroxidation in neurodegenerative diseases (ref: Wang doi.org/10.1038/s43587-021-00130-7/). These findings collectively emphasize the dual role of microglia in both protective and harmful responses during neuroinflammation, with implications for therapeutic strategies targeting microglial activation.

Microglial involvement in neurodegenerative diseases, particularly Alzheimer's disease (AD), has been extensively studied. The App knock-in rat model developed by Pang et al. provides a more accurate representation of AD pathology, exhibiting both Aβ and tau pathologies, neuronal death, and cognitive impairments, thus offering a valuable tool for future research (ref: Pang doi.org/10.1038/s41422-021-00582-x/). Jin et al. further elucidated the mechanisms by which tau activates microglia through the PQBP1-cGAS-STING pathway, leading to brain inflammation and cognitive decline, emphasizing the role of tau in neuroinflammatory processes (ref: Jin doi.org/10.1038/s41467-021-26851-2/). Additionally, Kummer et al. highlighted the protective role of astrocytic PD-L1 in suppressing neuroinflammation and AD pathology via microglial PD-1 stimulation, suggesting potential therapeutic targets for modulating immune responses in AD (ref: Kummer doi.org/10.15252/embj.2021108662/). These studies illustrate the complex interplay between microglia and other cell types in the context of neurodegeneration, revealing both detrimental and protective mechanisms that could be harnessed for therapeutic interventions.

The interactions between microglia and other cell types are pivotal in maintaining brain homeostasis and responding to injury. Recent research by Wallach et al. identified microRNA-100-5p and microRNA-298-5p released from apoptotic neurons as endogenous ligands for Toll-like receptors, which enhance microglial phagocytic activity and contribute to neurodegeneration (ref: Wallach doi.org/10.1186/s13024-021-00498-5/). Moreover, Smith et al. utilized single-nuclei RNA sequencing to reveal distinct transcriptional responses in astrocytes and microglia in Alzheimer's pathology, highlighting the differential roles these glial cells play in response to amyloid-beta and tau accumulation (ref: Smith doi.org/10.1007/s00401-021-02372-6/). Additionally, Morales et al. demonstrated that astrocytes play a protective role in removing axonal debris in Parkinson's disease, potentially preventing microglial activation and subsequent neuroinflammation (ref: Morales doi.org/10.1186/s40035-021-00262-1/). These findings underscore the importance of glial cell interactions in neuroinflammatory processes and their implications for neurodegenerative disease progression.

Microglia are increasingly recognized for their role in stress-related behavioral disorders. Lee et al. investigated the effects of social isolation on ethanol intake, revealing that microglia-derived neuroinflammation accelerates alcohol-seeking behaviors in a mouse model of isolation stress (ref: Lee doi.org/10.1126/sciadv.abj3400/). Hoshi et al. further explored the impact of stress-induced hyperthermia on neurogenesis, demonstrating that activation of TRPV4 in neural stem cells impairs hippocampal neurogenesis through microglial engulfment, linking stress responses to cognitive deficits (ref: Hoshi doi.org/10.1126/sciadv.abj8080/). Additionally, Zhang et al. highlighted the role of the p75 neurotrophin receptor in modulating neuroinflammation and promoting neurogenesis during Streptococcus pneumoniae meningitis, suggesting that microglial responses are critical in shaping outcomes in stress-related conditions (ref: Zhang doi.org/10.1186/s12974-021-02294-w/). These studies collectively illustrate the intricate relationship between microglial activation, stress, and behavioral outcomes, emphasizing the potential for targeting microglial pathways in treating stress-related disorders.

Microglia play a crucial role in the response to brain injury, with their activation influencing outcomes following various types of damage. d'Errico et al. demonstrated that microglia contribute to the propagation of Aβ into unaffected brain tissue, suggesting that their infiltration can exacerbate neurodegenerative processes (ref: d'Errico doi.org/10.1038/s41593-021-00951-0/). In the context of stroke, Shi et al. found that inhibiting microglial phagocytosis improved neurobehavioral outcomes in ischemic stroke, indicating that microglial activity can have both beneficial and detrimental effects depending on the injury context (ref: Shi doi.org/10.1038/s41467-021-27248-x/). Furthermore, Wang et al. highlighted the role of peroxidated lipids in activating the microglial NLRP3 inflammasome, leading to neuroinflammation and demyelination, which are critical in the progression of neurodegenerative diseases (ref: Wang doi.org/10.1038/s43587-021-00130-7/). These findings underscore the complex and context-dependent roles of microglia in brain injury, suggesting that targeted modulation of their activity could be a promising therapeutic strategy.

Microglia are integral to the immune response within the central nervous system, influencing both neuroinflammatory and neurodegenerative processes. Palmer et al. utilized single-nucleus RNA sequencing to investigate cellular and RNA isoform diversity in aging Down syndrome brains, revealing significant alterations that may contribute to cognitive impairments and neurodegenerative pathology (ref: Palmer doi.org/10.1073/pnas.2114326118/). Additionally, Wang et al. demonstrated that the Nogo receptor impairs microglial clearance of fibril Aβ, accelerating Alzheimer's-like disease progression, thus highlighting the importance of microglial function in maintaining brain health (ref: Wang doi.org/10.1111/acel.13515/). Chen et al. introduced a novel sporadic Alzheimer's disease model using acrolein, which induced classic AD pathologies, providing insights into the mechanisms underlying neuroinflammation (ref: Chen doi.org/10.1016/j.phrs.2021.106003/). These studies collectively emphasize the critical role of microglia in mediating immune responses in the brain and their potential as therapeutic targets for neurodegenerative diseases.