Microglial function plays a critical role in neurodegenerative diseases, particularly Alzheimer's disease (AD). Recent studies have highlighted the importance of the lipid phosphatase SHIP1, which limits complement-mediated synaptic pruning in the developing hippocampus, suggesting that SHIP1 may influence microglial activity and brain physiology (ref: Matera doi.org/10.1016/j.immuni.2024.11.003/). In models of AD, the activation of the integrated stress response (ISR) in microglia exacerbates neurodegenerative pathologies and synapse loss, while its inhibition can ameliorate these effects, indicating a potential therapeutic target (ref: Flury doi.org/10.1016/j.neuron.2024.11.018/). Furthermore, the deficiency of CD2AP in microglia has been shown to protect against cognitive and synaptic deficits in AD models, highlighting the complex interplay between microglial responses and amyloid-beta (Aβ) pathology (ref: Zhang doi.org/10.1186/s13024-024-00789-7/). The mechanisms by which microglia interact with Aβ are multifaceted. For instance, homeostatic microglia are essential for the initial seeding of Aβ plaques, while activated microglia later reshape these plaques, indicating a dual role in both plaque formation and resolution (ref: Baligács doi.org/10.1038/s41467-024-54779-w/). Additionally, microglia utilize a process termed digestive exophagy to degrade large Aβ deposits, which is crucial for maintaining neuronal health (ref: Jacquet doi.org/10.1016/j.celrep.2024.115052/). These findings underscore the necessity of understanding microglial function in the context of neurodegenerative diseases to develop effective therapeutic strategies.

Microglial activation and inflammation are pivotal in various neurodegenerative conditions, including Parkinson's disease (PD) and Alzheimer's disease (AD). A novel microgel system has been developed to manage PD by intervening in chemokine-mediated communication between nerve cells, demonstrating the potential for targeted therapeutic strategies that address neuroinflammation (ref: Jiang doi.org/10.1002/advs.202410070/). Furthermore, the study of high-speed two-photon fluorescence lifetime microscopy has advanced our understanding of neurodynamics, allowing for real-time monitoring of microglial and neuronal interactions in vivo, which is crucial for elucidating the inflammatory processes underlying neurodegeneration (ref: Li doi.org/10.1002/advs.202410605/). Accumulated branched-chain amino acids (BCAAs) and their metabolites have been implicated in the deterioration of AD through dysfunctional TREM2-mediated microglial clearance of Aβ, suggesting that metabolic dysregulation can exacerbate neuroinflammatory responses (ref: Yang doi.org/10.1186/s12974-024-03314-1/). Additionally, the deubiquitinating enzyme A20 has been shown to negatively regulate necroptosis-induced polarization of microglia/macrophages, highlighting the intricate balance of microglial activation states in response to neuronal injury (ref: Qiu doi.org/10.1038/s41419-024-07293-2/). These studies collectively emphasize the dual role of microglia in both promoting and resolving inflammation, which is critical for developing therapeutic approaches targeting microglial activation.

Microglia are increasingly recognized for their role in synaptic plasticity and repair mechanisms, particularly in the context of neurodegenerative diseases. Research indicates that homeostatic microglia are essential for the initial seeding of amyloid plaques in Alzheimer's disease, while activated microglia later contribute to the remodeling of these plaques, suggesting a dynamic role in both plaque formation and synaptic integrity (ref: Baligács doi.org/10.1038/s41467-024-54779-w/). Moreover, microglia have been shown to utilize digestive exophagy to degrade large Aβ deposits, which is vital for maintaining synaptic health and preventing neurodegeneration (ref: Jacquet doi.org/10.1016/j.celrep.2024.115052/). In addition to their role in AD, microglial Nrf2-mediated lipid and iron metabolism reprogramming has been identified as a crucial factor promoting remyelination during white matter ischemia, further underscoring their importance in repair processes (ref: Zhang doi.org/10.1016/j.redox.2024.103473/). The interplay between microglial activation and synaptic repair mechanisms is complex, as evidenced by the formation of foamy macrophages after spinal cord injury, which highlights the necessity of understanding the cellular context in which microglia operate (ref: Zhang doi.org/10.1016/j.redox.2024.103469/). These findings collectively illustrate the multifaceted roles of microglia in synaptic plasticity and repair, emphasizing their potential as therapeutic targets in neurodegenerative diseases.

Microglial interactions with other cell types are crucial for understanding their role in neuroinflammation and neurodegeneration. Tumor-associated microglia and macrophages (TAM) in glioblastoma have been shown to secrete extracellular ATP, promoting tumor progression and highlighting the protumoral signals that microglia can transmit to glioma cells (ref: Wu doi.org/10.1158/0008-5472.CAN-24-0018/). Additionally, the polarization of microglia and macrophages following cerebral ischemia is regulated by the deubiquitinating enzyme A20, which inhibits necroptosis and thus influences the inflammatory response (ref: Qiu doi.org/10.1038/s41419-024-07293-2/). The interaction between microglia and astrocytes is also significant, particularly in the context of blood-brain barrier (BBB) integrity. A novel annexin dimer has been identified that targets microglial phagocytosis of astrocytes, which is essential for protecting the BBB after cerebral ischemia (ref: Tang doi.org/10.1038/s41401-024-01432-3/). Furthermore, focused ultrasound-mediated disruption of the BBB has been explored for its effects on inflammation, revealing that treatment parameters can influence microglial activation and neurovascular function (ref: Angolano doi.org/10.1016/j.biopha.2024.117762/). These studies underscore the importance of microglial interactions with other cell types in modulating inflammatory responses and maintaining CNS homeostasis.

Microglia are increasingly recognized for their role in cognitive disorders, particularly in Alzheimer's disease and depression. The lipid phosphatase SHIP1 has been implicated in limiting complement-mediated synaptic pruning, which is crucial for maintaining cognitive function during brain development (ref: Matera doi.org/10.1016/j.immuni.2024.11.003/). Additionally, microglia-derived vitamin D binding protein (VDBP) has been shown to mediate synaptic damage and induce depression-like behaviors by interacting with the neuronal receptor megalin, suggesting a pathway through which microglial dysfunction can contribute to cognitive decline (ref: Kong doi.org/10.1002/advs.202410273/). Moreover, the accumulation of branched-chain amino acids (BCAAs) and their metabolites has been linked to the deterioration of cognitive function in Alzheimer's disease through impaired microglial clearance of Aβ, indicating that metabolic factors can exacerbate cognitive disorders (ref: Yang doi.org/10.1186/s12974-024-03314-1/). The interplay between microglial activation, synaptic integrity, and cognitive function highlights the need for further research into therapeutic strategies targeting microglial pathways to mitigate cognitive decline in neurodegenerative diseases.

Microglial responses to environmental stressors play a significant role in neuroinflammation and neurodegeneration. For instance, metformin has been shown to attenuate central sensitization in chronic migraine models by regulating neuroinflammation through the TREM2-SYK signaling pathway, highlighting a potential therapeutic avenue for managing pain and inflammation (ref: Fan doi.org/10.1186/s12974-024-03313-2/). Additionally, prolonged ozone exposure has been demonstrated to activate olfactory bulb microglia, leading to neuronal pyroptosis and cognitive dysfunction, illustrating how environmental toxins can trigger detrimental microglial responses (ref: Xu doi.org/10.1016/j.jhazmat.2024.136901/). The characterization of focused ultrasound-mediated blood-brain barrier disruption has revealed that treatment parameters can significantly influence inflammation and microglial activation, suggesting that such interventions must be carefully calibrated to avoid adverse effects (ref: Angolano doi.org/10.1016/j.biopha.2024.117762/). These findings underscore the importance of understanding microglial responses to environmental stressors in developing effective therapeutic strategies for neurodegenerative diseases.

Therapeutic strategies targeting microglia are gaining traction in the field of neurodegenerative disease research. One promising approach involves the use of a microgel system designed to manage Parkinson's disease by intervening in chemokine-mediated communication between nerve cells, potentially reducing neuroinflammation and promoting neurogenesis (ref: Jiang doi.org/10.1002/advs.202410070/). Additionally, the deubiquitinating enzyme A20 has been identified as a key regulator of microglial polarization and necroptosis, suggesting that modulating A20 activity could mitigate cerebral injury and improve outcomes after ischemic events (ref: Qiu doi.org/10.1038/s41419-024-07293-2/). Furthermore, the accumulation of branched-chain amino acids (BCAAs) has been linked to impaired microglial clearance of amyloid-beta, indicating that metabolic interventions may enhance microglial function and slow the progression of Alzheimer's disease (ref: Yang doi.org/10.1186/s12974-024-03314-1/). These studies highlight the potential for developing targeted therapies that harness microglial functions to combat neurodegenerative diseases and improve patient outcomes.